Compositions, gels and foams with rheology modulators and uses thereof

ABSTRACT

The present disclosure relates generally to compositions for cosmetic or pharmaceutical application. The compositions include a carrier and rheology modulators.APP

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 13/100,724, filed May 4, 2011.

U.S. application Ser. No. 13/100,724, filed May 4, 2011, is acontinuation-in-part application of International Application No.PCT/IB2010/002612, filed Oct. 1, 2010, and entitled “Surfactant-FreeWater-Free Foamable Compositions, Breakable Foams and Gels, and TheirUses,” which claims the benefit of priority to U.S. ProvisionalApplication No. 61/248,144, filed Oct. 2, 2009, and entitled“Surfactant-Free Water-Free Foamable Compositions, Breakable Foams andTheir Uses;” U.S. Provisional Application No. 61/322,148, filed Apr. 8,2010, and entitled “Surfactant-Free Water-Free Foamable Compositions,Breakable Foams and Their Uses;” U.S. Provisional Application No.61/349,911, filed May 31, 2010, and entitled “Surfactant-Free Water-FreeFoamable Compositions, Breakable Foams and Their Uses;” U.S. ProvisionalApplication No. 61/385,385, filed Sep. 22, 2010, and entitled“Surfactant-Free Water-Free Foamable Compositions, Breakable Foams andGels and Their Uses;” U.S. Provisional Application No. 61/331,126, filedMay 4, 2010, and entitled “Compositions, Gels and Foams with RheologyModulators and Uses Thereof;” U.S. Provisional Application No.61/388,884, filed Oct. 1, 2010, and entitled “Compositions, Gels andFoams With Rheology Modulators and Uses Thereof”; and U.S. ProvisionalApplication No. 61/380,568, filed Sep. 7, 2010, and entitled“Surfactant-Free Water-Free Foamable Compositions and Breakable Foamsand Their Uses; all of which are herein incorporated in their entiretyby reference.

U.S. application Ser. No. 13/100,724, filed May 4, 2011, is acontinuation-in-part application of International Application No.PCT/IB2010/002617, filed Oct. 1, 2010, and entitled “TopicalTetracycline Compositions” which claims the benefit of priority to U.S.Provisional Application No. 61/248,144, filed Oct. 2, 2009, and entitled“Surfactant-Free Water-Free Foamable Compositions, Breakable Foams andTheir Uses;” United States Provisional Application No. 61/322,148, filedApr. 8, 2010, and entitled “Surfactant-Free Water-Free FoamableCompositions, Breakable Foams and Their Uses;” U.S. ProvisionalApplication No. 61/349,911, filed May 31, 2010, and entitled“Surfactant-Free Water-Free Foamable Compositions, Breakable Foams andTheir Uses;” U.S. Provisional Application No. 61/385,385, filed Sep. 22,2010, and entitled “Surfactant-Free Water-Free Foamable Compositions,Breakable Foams and Gels and Their Uses;” U.S. Provisional ApplicationNo. 61/331,126, filed May 4, 2010, and entitled “Compositions, Gels andFoams with Rheology Modulators and Uses Thereof;” U.S. ProvisionalApplication No. 61/388,884, filed Oct. 1, 2010, and entitled“Compositions, Gels and Foams With Rheology Modulators and UsesThereof”; and U.S. Provisional Application No. 61/380,568, filed Sep. 7,2010, and entitled “Surfactant-Free Water-Free Foamable Compositions andBreakable Foams and Their Uses; all of which are herein incorporated intheir entirety by reference.

U.S. application Ser. No. 13/100,724, filed May 4, 2011, is acontinuation-in-part application of International Application No.PCT/IB2010/002613, filed Oct. 1, 2010, and entitled “Surfactant-FreeWater-Free Foamable Compositions, Breakable Foams and Their Uses” whichclaims the benefit of priority to U.S. Provisional Application No.61/248,144, filed Oct. 2, 2009, and entitled “Surfactant-Free Water-FreeFoamable Compositions, Breakable Foams and Their Uses; U.S. ProvisionalApplication No. 61/322,148, filed Apr. 8, 2010, and entitled“Surfactant-Free Water-Free Foamable Compositions, Breakable Foams andTheir Uses; U.S. Provisional Application No. 61/349,911, filed May 31,2010, and entitled “Surfactant-Free Water-Free Foamable Compositions,Breakable Foams and Their Uses; U.S. Provisional Application No.61/385,385, filed Sep. 22, 2010, and entitled “Surfactant-FreeWater-Free Foamable Compositions, Breakable Foams and Gels and TheirUses; U.S. Provisional Application No. 61/331,126, filed May 4, 2010,and entitled “Compositions, Gels and Foams with Rheology Modulators andUses Thereof; U.S. Provisional Application No. 61/388,884, filed Oct. 1,2010, and entitled “Compositions, Gels and Foams With RheologyModulators and Uses Thereof”; and U.S. Provisional Application No.61/380,568, filed Sep. 7, 2010, and entitled “Surfactant-Free Water-FreeFoamable Compositions and Breakable Foams and Their Uses; all of whichare herein incorporated in their entirety by reference.

BACKGROUND

The term rheology, describes the flow dynamics of liquids and thedeformation of solids. Rheological properties of heterogeneousdispersions are complex and cannot be expressed in a single parameter.Manufacturers of medicinal and cosmetic gels, creams, pastes, lotionsand foams must be capable of producing products with acceptableconsistency and smoothness and reproducing these qualities each time anew batch is prepared including its look, feel, body, and consistency.

Rheology is involved in the mixing and flow of materials, theirpackaging into containers, and their dispensing prior to use, whetherthis is achieved by pouring from a bottle, extrusion from a tube,passage through a syringe needle, or extrusion through a valve. Therheology of a particular product, which can range in consistency fromfluid to semisolid to solid, can affect its patient acceptability,physical stability, and even biologic availability. For example,viscosity which is a rheological property has been shown to affectabsorption rates of drugs.

Pharmaceutical areas, in which rheology is significant include productdesign and processing are fluids, quasi-solids, solids, and processing.Rheology of fluids is pertinent in respect of: (a) mixing fluids; (b)reduction of systems with shear; (c) passage through orifices, includingpouring, packaging in bottles, passage through hypodermic needles andpassage through valves; (d) fluid transfer, including pumping and flowthrough pipes; and (e) physical stability of disperse systems. Rheologyof quasi-solids or semi-solids is pertinent including in respect of: (a)spreading and adherence on the skin; (b) removal from jars or extrusionfrom tubes; (c) capacity of solids to mix with miscible liquids; and (d)release of the drug from the base.

When classifying materials according to types of flow and deformation,it is customary to place them in one of two categories: Newtonian ornon-Newtonian systems. The choice depends on whether or not their flowproperties are in accord with Newton's law of flow. Newton recognizedthat the higher the viscosity of a liquid, the greater is the force perunit area (shearing stress) required to produce a certain rate of shear.Many fluid pharmaceutical products behave as Non-Newtonian systems.

Rheological properties such as tackiness or stickiness, “body,” “slip,”and “spreadability” are difficult to measure by means of conventionalapparatus and, in fact, do not have precise meanings. Whereas,viscosity, yield value, thixotropy, and the other properties thatcontribute to the total consistency of non-Newtonian pharmaceuticals canbe analyzed.

Viscosity is a measure of the internal resistance of a fluid to flowwhich is being deformed by either shear stress or tensile stress; thehigher the viscosity, the greater is the resistance. Simple liquids canbe described in terms of absolute viscosity. In everyday terms (and forfluids only), viscosity is “thickness” and may be thought of as anindication of fluid friction. Shear viscosity, describes the reaction toapplied shear stress; in other words, it is the ratio between thepressure exerted on the surface of a fluid, in the lateral or horizontaldirection, to velocity gradient.

Gels are jelly-like material that can have properties ranging from softand fluid to hard and tough. Gels may be in liquid, semi-liquid or solidstate. Solid gels are defined as a substantially diluted crosslinkedsystem, which exhibits no flow when in the steady-state. By weight, gelsare mostly liquid, yet they behave like semi-solids due to athree-dimensional crosslinked network of a solidifying, gelling orthickening agent within the liquid. It is the crosslinks within thefluid that give a gel its structure (hardness) and contribute tostickiness (tack). Depending on the amounts of gelling agents in aformulation the gel may be semi solid with some limited flowability,such that when the semi-solid gel is placed in a tube and is inclinedhorizontally from a vertical position it will slowly flow from thevertical towards the horizontal or it may be a liquid gel where theamount of gelling agents or gelling effect is lower such that the gelstructure or connections are weaker or loose so that when placed in atube and tilted from a vertical position to the horizontal the gelreadily flows and adapts to the horizontal position. The rheologicalproperties of gels at different surface temperatures can influence therelease and bioabsorption of drugs therefrom.

It is a desirable property for composition for topical use to havecontrollable viscosity. High viscosity is required to avoid drips andruns for ease of application and improve suspending properties in orderto avoid rapid sedimentation of non-dissolved active ingredients.Whereas, low viscosity is desirable to enable spreadability and goodflow properties. The less viscous something is, the greater its ease ofmovement (fluidity). A delicate balance between these two attributes issought out in accordance with the intended use of the compositions. Thisbalance is difficult to attain as viscosity of a composition isinfluenced by different factors such as reaction or interaction betweendifferent components under different temperature and pressureconditions.

Thickening or solidifying agent or solidifying complexes are materialsadded to a composition which increase viscosity and retardsedimentation. The use of waxes, fatty alcohols, fatty acids and 12hydroxy stearic acid, in solidifying oils is known. Pharmaceuticalcompositions having a netted framework, comprising an oil and beeswax asa gelling agent that form a film after application on a body surface arealso known. Netted frameworks and/or films can be in certaincircumstances be a disadvantage.

The addition of a fatty alcohol, or a fatty acid, or both to a liquidoil also gives rise to thixotropic properties (e.g., being semi-solid atrest and liquid upon application of shear forces thereto). This propertyenables application of a thixotropic mixture as a semi-solid state to abody surface, which subsequently becomes substantially liquid andtherefore more spreadable and penetrable when rubbed onto the bodysurface. Thus, they are semi-solid at rest and that they liquefy uponapplication of shear forces thereto. Semi-solid hydrophobic formulationsare important not only for the pharmaceutical market but also forcosmetic products, such as carriers of sunscreen compounds, oil-solubleplant extracts, materials for scrubbing purposes and other active andnon-active cosmetic ingredients.

Foams and, in particular, single-phase oleaginous foams are complicatedsystems which do not form under all circumstances. Slight shifts in foamcomposition, such as by the addition of active agents or the removal ofany of the essential ingredients, may destabilize the foam. The priorart teaches that oleaginous foam compositions require significantamounts of surface active agents to form a foam. These compositionsrequire various standard surfactants, as essential components.

Surfactants are known as essential ingredients in foam compositions; andspecifically in oleaginous foams. However, many surfactants are known tobe irritating when left on the skin can also react with unstable activeagents and lead to their rapid degradation.

Gels and foams are not pharmaceutically equivalent, unless theircomposition upon administration is similar.

SUMMARY

The present application relates to compositions comprising a carrier anda first and second rheology modulator or modulator (usedinterchangeably). The application also relates to compositions orfoamable compositions and foam without surfactants and/or withoutpolymeric agents comprising an oleaginous carrier, a first rheologymodulator which is a suspended pharmaceutical or cosmetic active agent(referred as “active agent”) and second rheology modulator consisting ofat least one fatty alcohol, at least one fatty acid, at least one waxand mixtures of two or more thereof. Solid fatty alcohols and/or fattyacids and/or waxes were carefully selected through experimentation assuitable thickening agents, which can be compatible with unstable activeagents.

It was surprisingly discovered that the addition of a very lowconcentration of a suspended active agent into a composition orformulation comprising a hydrophobic solvent, together with a secondrheology modulator, which may be at least one fatty alcohol or at leastone fatty acid, and/or at least one wax and mixtures of two or morethereof dramatically modulates the rheological properties of thecomposition and in particular can synergistically increase the viscosityof a composition, thereby providing improved usability of thecomposition.

It was further surprisingly discovered in the present invention, thatcertain compositions comprising a hydrophobic solvent, together with asecond rheology modulator, which may be at least one fatty alcohol or atleast one fatty acid, and/or at least one wax and mixtures of two ormore thereof; and a suspended active agent without any surface activeagents resulted, upon packaging in an aerosol container and adding apropellant, in a shakable and homogenous foamable composition, whichreleased a breakable foam with good to excellent quality (as definedherein).

The resulting foam is pharmaceutically equivalent to the respective gel(prior to adding the propellant), since immediately upon dispensing ofthe foam the propellant evaporates and the composition uponadministration is similar to that of the gel. This is an importantpragmatic advantage, because many drug development activities, includingexpensive and lengthy clinical trials on thousands of patients, can besaved by conducting such studies once for both the gel and foam insteadof twice.

In one or more embodiments there is provided a composition for cosmeticor pharmaceutical application comprising:

-   -   a) a first rheology modulator comprising a suspended        pharmaceutical active agent or a suspended cosmetic active        agent;    -   b) a second rheology modulator comprising at least one fatty        alcohol, at least one fatty acid, at least one wax and mixtures        thereof and    -   c) a hydrophobic carrier comprising at least one hydrophobic        solvent;    -   wherein the viscosity of the composition is at least about 30%        higher than the viscosity of a first partial composition        comprising the second rheology modulator agent and the        hydrophobic carrier without the first rheology modulator; and is        higher than the viscosity of a second partial composition        comprising the first rheology modulator and the hydrophobic        carrier without the second rheology modulator; and

In certain embodiments, the viscosity of the first partial compositionis less than about 25,000 cPs at room temperature.

According to an another embodiment the composition further comprisesabout 1% to about 25% by weight of a polar solvent or a penetrationenhancer.

In one or more embodiments the first rheology modulator comprises atleast one tetracycline. In one or more embodiments the tetracycline iscompatible with the carrier and with the second rheology modulator.

In one or more embodiments the amount of first rheology modulator is atherapeutically effective amount. In one or more embodiments the firstrheology modulator is a suspended active agent.

In one or more embodiments the active agent is a tetracycline. In one ormore embodiments the tetracycline is tetracycline, oxytetracycline,demeclocycline, doxycycline, lymecycline, meclocycline, methacycline,minocycline, rolitetracycline, chlorotetracycline or tigecycline. In oneor more embodiments the tetracycline is tetracycline, minocycline ordoxycycline or a salt thereof. In one or more embodiments thetetracycline is a mixture of two or more tetracyclines. In one or moreembodiments the tetracycline is a hydrophobic tetracycline, selectedfrom minocycline and doxycycline. In one or more embodiments it is amixture of both. In one or more embodiments the tetracycline is presentin a free base form, a hydrate form, a salt form or a complex form. Inone or more embodiments at least part of the tetracycline is not solubleand is suspended in the composition. A tetracycline that is suitable asa first rheology modulator according to the present invention is onethat is not soluble or is partially soluble and all or part thereof issuspended in the composition.

In one or more embodiments the better rheology includes one or more of areduction in composition flow, an increase in composition viscosity, anincrease in hardness, or an increase in adhesion, and/or thixotropy, orany two or more thereof.

Viscosity is raised significantly when a formulation comprising beeswaxin combination with another wax or a fatty acid or fatty alcohol in ahydrophobic carrier is challenged with a first rheology active agent(minocycline).

In one or more embodiments there is provided a composition wherein theviscosity of the composition changes with time whilst the composition isflowing. In certain embodiments the change is an increase. In certainother embodiments the change is a decrease. In some embodiments thecomposition is not flowing.

In one or more embodiments upon addition of the first rheology modulatorto a composition comprising a second rheology modulator the compositionbecomes more viscous. An example is where a tetracycline antibiotic isadded to a fatty alcohol in an oil carrier [see Examples 4 and 5].

In one or more embodiments there is provided a composition in which thefirst and second rheology modulators act synergistically. In one or moreembodiments the first and second modulators act synergistically toincrease the viscosity of the composition.

In one or more embodiments there is provided a composition in which theviscosity of the composition after addition of the first rheologymodulator and second rheology modulator to the carrier is higher thanthe viscosity of the composition with the second modulator agent to thecarrier, without the first modulator; and is higher than the viscosityof the composition with the first modulator to the carrier without thesecond modulator.

In an embodiment or more embodiments there is provided a composition asa vehicle or carrier wherein by adding an active agent to a compositioncomprising a second rheology modulator one or more rheologicalproperties of the composition are modulated such as the viscosity of thecomposition is changed (e.g., increased substantially).

In one or more embodiments, there is provided an oleaginous formulationcomprising a hydrophobic solvent, such as mineral oil(s) and at leastone suspended active agent which is a tetracycline in synergisticcombination with a second rheology modulator comprising a fatty alcoholand/or a fatty acid and/or a wax.

A composition comprising the second rheology modulator and thehydrophobic carrier without the first rheology modulator is designated afirst partial composition and a composition comprising the firstrheology modulator and the hydrophobic carrier without the secondrheology modulator is designated a second partial composition. In one ormore embodiments the viscosity of the composition is at least about 50%more than the viscosity of the first partial composition without thefirst rheology modulator. In one or more embodiments the increase inviscosity of the composition is at least about 100% more than theviscosity of the first partial composition without the first rheologymodulator. In one or more embodiments the increase in viscosity of thecomposition is at least about 100% and viscosity of the first partialcomposition without the first rheology modulator is less than about12,000 cPs; or less than about 8,000 cPs; or less than about 2,000 cPs.In one or more embodiments the viscosity of the first partialcomposition without the first rheology modulator is more than about1,000 cPs; or more than about 1,300 cPs; or more than about 1,500 cPs.or more than about 1,800 cPs or more than about 2000 cPs.

In certain embodiments the increase in viscosity is a synergisticincrease such that the combined viscosity of the first partialcomposition and the viscosity of the second partial composition is lessthan the viscosity of the composition.

In one or more embodiments the change in viscosity is at least about 20%or more than 20%. In one or more embodiments the change in viscosity isat least about 30% or more than 30%. In one or more embodiments thechange in viscosity is at least about 40% or more than 40%. In one ormore embodiments the change in viscosity is at least about 50% or morethan 50%. In one or more embodiments the change in viscosity is at leastabout 100% or more than 100%. In one or more embodiments the change inviscosity is at least about 150% or more than 150%. In one or moreembodiments the change in viscosity is at least about 200% or more than200%. In one or more embodiments the change in viscosity is at leastabout 250% or more than 250%. In one or more embodiments the change inviscosity is at least about 300% or more than 300%. In one or moreembodiments the change in viscosity is at least about 350% or more than350%. In one or more embodiments the change in viscosity is at leastabout 400% or more than 400%. In one or more embodiments the change inviscosity is at least 450% or at least more than 450%. In one or moreembodiments the change in viscosity is at least about 500% or more than500%. In one or more embodiments the change in viscosity is at leastabout 1000% or more than 1000%. In one or more embodiments the change inviscosity is at least about 1500% or more than 1500%. %. In one or moreembodiments the change in viscosity is at least about 2000% or more than2000%. In one or more embodiments the change in viscosity is at leastabout 2500% or more than 2500%. In one or more embodiments the change inviscosity is at least about 20% or more than 20%. In one or moreembodiments the change in viscosity is at least about 30% or more than30%. In one or more embodiments the change in viscosity is at leastabout 40% or more than 40%. In one or more embodiments the change inviscosity is between about 50% and about 100%. In one or moreembodiments the change in viscosity is between about 100% and about500%. In one or more embodiments the change in viscosity is betweenabout 500% and about 1000%. In one or more embodiments the change inviscosity is between about 1000% and about 1500%. In one or moreembodiments the change in viscosity is between about 1500% and about2000%. In one or more embodiments the change in viscosity is betweenabout 2000% and about 2500%. In one or more embodiments the change inviscosity is between about 50% and about 3000%. In one or moreembodiments the change in viscosity is in a range between about 150% andabout 1000%. In one or more embodiments the change in viscosity is in arange between about 1000% and about 2500% In one or more embodiments thechange in viscosity is between about 100% and about 2500%; about 100%and about 2000%; about 100% and about 1500%; or about 100% and about1000%.

In one or more embodiments the viscosity of the carrier and thecomposition prior to the addition of the first rheology modulator(namely the first partial composition) is less than about 30,000 cPs. Inone or more embodiments the viscosity of the carrier and the compositionprior to the addition of the first rheology modulator is less than about25,000 cPs. In one or more embodiments the viscosity of the carrier andthe composition prior to the addition of the first rheology modulator isless than about 20,000 cPs. In one or more embodiments the viscosity ofthe carrier and the composition prior to the addition of the firstrheology modulator is less than about 15,000 cPs. In one or moreembodiments the viscosity of the carrier and the composition prior tothe addition of the first rheology modulator is less than about 12,000cPs. In one or more embodiments the viscosity of the carrier is lessthan about 10,000 cPs. In one or more embodiments the viscosity of thecarrier and the composition prior to the addition of the first rheologymodulator is less than about 8,000 cPs. In one or more embodiments theviscosity of the carrier and the composition prior to the addition ofthe first rheology modulator is less than about 6,000 cPs. In one ormore embodiments the viscosity of the carrier and the composition priorto the addition of the first rheology modulator is less than about 5,000cPs. In one or more embodiments the viscosity of the carrier and thecomposition prior to the addition of the first rheology modulator isless than about 4,000 cPs. In one or more embodiments the viscosity ofthe carrier and the composition prior to the addition of the firstrheology modulator is less than about 3,000 cPs. In one or moreembodiments the viscosity of the carrier and the composition prior tothe addition of the first rheology modulator is less than about 2,000cPs. In one or more embodiments the viscosity of the carrier and thecomposition prior to the addition of the first rheology modulator isless than about 1,000 cPs. In one or more embodiments the viscosity ofthe carrier and the composition prior to the addition of the firstrheology modulator is less than about 500 cPs. In one or moreembodiments the viscosity of the carrier and composition prior to theaddition of the first rheology modulator is less than about 30,000 cPs;is less than about 25,000 cPs; is less than about 20,000 cPs; is lessthan about 15,000 cPs; is less than about 12,000 cPs; is less than about10,000 cPs; is less than about 8,000 cPs; is less than about 6,000 cPs;is less than about 5,000 cPs; is less than about 4,000 cPs; is less thanabout 3,000 cPs; is less than about 2,000 cPs; is less than about 1,000cPs; or is less than about 500 cPs. In one or more embodiments theviscosity of the carrier and the composition prior to the addition ofthe first rheology modulator is less than about 30,000 cPs; is less thanabout 25,000 cPs; is less than about 20,000 cPs; is less than about15,000 cPs; is less than about 12,000 cPs; is less than about 10,000cPs; is less than about 8,000 cPs; is less than about 6,000 cPs; is lessthan about 5,000 cPs; is less than about 4,000 cPs; is less than about3,000 cPs; is less than about 2,000 cPs; is less than about 1,000 cPs;or is less than about 500 cPs. In one or more embodiments the viscosityrange of the carrier or the composition prior to the addition of thefirst rheology modulator or the carrier and the composition prior to theaddition of the first rheology modulator includes about 30,000 cPs toabout 1,000 cPs; about 25,000 cPs to about 1,000 cPs; about 20,000 cPsto about 1,000 cPs; about 12,000 cPs to about 1,000 cPs; about 10,000cPs to about 1,000 cPs; about 8,000 cPs to about 1,000 cPs; about 6,000cPs to about 1,000 cPs; about 5,000 cPs to about 1,000 cPs; about 4,000cPs to about 1,000 cPs; about 2,000 cPs to about 1,000 cPs; or about2,000 cPs to about 500 cPs; about 25,000 cPs to about 500 cPs; about20,000 cPs to about 500 cPs; about 12,000 cPs to about 500 cPs; about10,000 cPs to about 500 cPs; about 8,000 cPs to about 500 cPs; about6,000 cPs to about 500 cPs; about 6,000 cPs to about 150 cPs; about4,000 cPs to about 150 cPs; about 2,000 cPs to about 150 cPs; or about1,000 cPs to about 150 cPs;

In one or more embodiments there is provided a composition in which theactive agent is in an amount that is capable of altering the viscosityof the composition to a level higher than the viscosity of thecomposition prior to the addition of the active agent and wherein thesecond rheology modulator is capable of altering the viscosity of thecomposition before, upon or following the addition of the firstmodulator.

In one or more embodiments the composition is substantially waterless.

In one or more embodiments the composition is a liquid or freelyflowable. In one or more embodiments the composition is a semi solid. Inone or more embodiments the composition is a thick gel.

In one or more embodiments the composition is essentially free of one ormore of the following:

a) Water;

b) Polymeric agent;

c) Surfactant;

d) Short chain alcohol;

e) Polyol;

In one or more embodiments the composition is essentially free of two ormore of water; polymeric agent; surfactant; short chain alcohol; orpolyol. In one or more embodiments the composition is essentially freeof three or more of water; polymeric agent; surfactant; short chainalcohol; or polyol. In one or more embodiments the composition isessentially free of four or more of water; polymeric agent; surfactant;short chain alcohol; or polyol. In one or more embodiments thecomposition is essentially free of water; polymeric agents; surfactants;short chain alcohols; and polyols.

For example, in one or more embodiments the composition is essentiallyfree of water, polymeric agents, surfactants, short chain alcohol andpolyols. In one or more embodiments the composition is essentially freeof polymeric agents, surfactants, short chain alcohol and polyols. Inone or more embodiments the composition is essentially free of water,surfactants, short chain alcohols and polyols. In one or moreembodiments the composition is essentially free of water, polymericagents, short chain alcohols and polyols. In one or more embodiments thecomposition is essentially free of water, polymeric agents, surfactantsand polyols. In one or more embodiments the composition is essentiallyfree of water, polymeric agents, surfactants and short chain alcohols.

In one or more embodiments there is provided a composition in which thecomposition has one two or three the following characteristics:

a) Provides for chemical stability of the active agent in thecomposition;

b) Provides for physical stability of the composition;

c) Provides a therapeutic effect;

In one or more embodiments there is provided a composition in which theactive agent is stable at room temperature for at least 1 month, or atleast 2 months, or at least 3 months, or at least 4 months, or at least5 months, or at least 6 months, or at least 12 months, or at least 18months. In one or more embodiments there is provided a composition inwhich the active is stable at 40° C. for at least 1 month, or at least 2months, or at least 3 months, or at least 4 months, or at least 5months, or at least 6 months.

In one or more embodiments there is provided a composition in which theactive agent forms a complex with one or more excipients.

In one or more embodiments there is provided a composition in which theactive agent is chemically stable in the presence of the second rheologymodulator and/or the carrier.

In one or more embodiments there is provided a composition in which thesuspended active agent is selected from a list comprising atetracycline, mometasone furoate, doxycycline hyclate, salicylic acid,diclofenac, urea, terbinafine, permethrin, metronidazole, pimecrolimusand benzoyl peroxide.

In one or more embodiments certain active agent, which are fully solublein the composition including cholesterol and vitamin E also demonstratea synergistic viscosity increase.

In one or more embodiments there is provided a composition in which therheology modulator is selected from the group comprising a fattyalcohol, a fatty acid, beeswax, beeswax extract, a paraffin wax andhydrogenated castor oil and mixture thereof.

In one or more embodiments there is provided a composition in which thesecond rheology modulator comprises at least one fatty alcohol, or atleast one fatty acid or least one wax or mixtures of two or morethereof.

In one or more embodiments there is provided a composition in which thesecond rheology modulator comprises a combination of (i) at least onefatty alcohol, (ii) at least one fatty acid; and (iii) at least one wax.

In one or more embodiments there is provided a composition in which thesecond rheology modulator comprises a compound, selected from the groupsconsisting of at least one fatty alcohol, at least one fatty acid, atleast one wax and mixtures of two or more thereof. At least one fattyalcohol is selected from the group consisting of (a) a fatty alcoholhaving 14 or more carbons in their carbon chain, myristyl alcohol, cetylalcohol, stearyl alcohol, erucyl alcohol, arachidyl alcohol, behenylalcohol, tetracosanol, hexacosanol, octacosanol, triacontanol,tetratriacontanol, 1-triacontanol and a fatty alcohol, having a carbonchain between C30 and C50, (b) a fatty alcohol mixture, derived frombeeswax, (c) a therapeutically-active fatty alcohol. At least one fattyacid is selected from the group consisting of a hydroxy fatty acid, afatty acid having 12 or more carbons in its carbon chain, dodecanoicacid, myristic acid, hexadecanoic acid, heptadecanoic acid, stearicacid, arachidic acid, behenic acid, tetracosanoic acid, hexacosanoicacid, heptacosanoic acid, octacosanoic acid, triacontanoic acid,dotriacontanoic acid, tritriacontanoic acid, tetratriacontanoic acid andpentatriacontanoic acid and a fatty acid, having a carbon chain betweenC30 and C50. At least one wax is selected from the group consisting of:a wax, having the properties of (i) plastic behavior at ambienttemperatures, (ii) a melting point above approximately 45° C., (iii) arelatively low viscosity when melted; and (iv) hydrophobic nature;

In one or more embodiments the composition further comprises a liquefiedor compressed gas propellant wherein the composition is a foamablecomposition;

wherein the second rheology modulator is about 0.1% to about 20% byweight of the composition; wherein the hydrophobic carrier is about 60%to about 95% by weight of the composition and wherein the ratio ofcomposition other than propellant to propellant is from about 100:1 toabout 100:30; and wherein upon dispensing the foamable carriercomposition forms a breakable foam that breaks easily upon applicationof shear force. In an embodiment the formulation is short term stable.

In one or more embodiments, the formulation is a gel that is capable offorming a foamable composition when packaged into an aerosol canister,equipped with a valve and pressurized with a liquid or pressurized gaspropellant and is capable of releasing a foam of quality that isbreakable upon application of shear force but is not thermolabile atabout or close to body temperature (about 36° C.).

In one or more embodiments, upon addition of between about 4% to about8%; or about 8% to about 12% propellant, the formulations provide a foamof good or excellent quality that had a collapse time in excess of 3minutes.

In an embodiment the wax is selected from the group consisting ofvegetable wax, beeswax, chinese wax, cotton wax, bayberry wax,candelilla wax, carnauba wax, castor wax, cuban palm wax, esparto wax,fir wax, flax wax, flower wax, fat wax, japan wax, sandy wax, lanolinwax, ouricury wax, palm waxes, rice bran wax, rice-oil wax, shellac wax,soy wax, sugar cane wax, ucuhuba wax, a hydrogenated oil, hydrogenatedcastor oil, hydrogenated cottonseed oil, or hydrogenated jojoba oil,mink wax, montan wax, ozokerite, PEG-6 beeswax, rezo wax, spent grainwax, stearyl dimethicone, a paraffin wax, paraffin 58-62° C. wax,paraffin 51-53° C. wax, paraffin 42-44° C. wax, synthetic mineral wax,fischer-tropsch wax, duroxon wax, or polymekon wax, synthetic waxes,albacer wax, atlasene wax, BASF waxes, cardis waxes, ceramid, glycowaxes, flexo wax, or oxazoline waxes, as well as other waxes, asdescribed in “The Complete Technology Book on Wax and Polishes,Publisher: Asia Pacific Business Press Inc., 2006”.

In one or more embodiments the wax is a mixture of two or more waxes. Incertain embodiments the mixture of waxes comprises hydrogenated casteroil and beeswax.

In one or more embodiments the ratio of fatty alcohol to wax or fattyacid to wax or fatty alcohol and fatty acid to wax can be between about1:10 to about 10:1. In one or more embodiments the ratio of fattyalcohol to wax or fatty acid to wax or fatty alcohol and fatty acid towax can be between about 1:5 to about 5:1. In one or more embodimentsthe ratio of fatty alcohol to wax or fatty acid to wax or fatty alcoholand fatty acid to wax can be between about 1:3 to about 3:1. In one ormore embodiments the ratio of fatty alcohol to wax or fatty acid to waxor fatty alcohol and fatty acid to wax can be between about 1:2 to about2:1. In one or more embodiments the ratio of fatty alcohol to wax orfatty acid to wax or fatty alcohol and fatty acid to wax can be about1:1.

In one or more embodiments there is provided a composition in whichcholesterol has a rheology effect, wherein it acts as a viscositybooster.

In one or more embodiments there is provided a composition in which theconcentration of the first rheology modulator in the composition is fromabout 0.01% to about 25% by weight.

The composition comprises at least one hydrophobic solvent

In one or more embodiments the hydrophobic solvent is selected from thegroup consisting of a diglyceride, a therapeutic oil, acetylated lanolinalcohol, alexandria laurel tree oil, alkyl benzoate, alkyl octanoate,almond oil, an essential oil, an unsaturated or polyunsaturated oil,apricot stone oil, arachidyl behenate, arachidyl propionate, avocadooil, barley oil, basil oil, beeswax, benzyl laurate, benzyl myristate,benzyl palmitate, bis (octyldodecyl stearoyl) dimer dilinoleate, borageseed oil, butyl myristate, butyl stearate, C12-C15 alkyl benzoate,C12-C15 alkyl octanoate, calendula oil, camphor oil, canelle nut treeoil, canola oil, capric/caprylic triglycerides, caprylic/caprictriglyceride castor oil, caprylyl methicone, cardamom oil, carrot oil,castor oil, cetearyl ethylhexanoate, cetearyl isononanoate, cetearyloctanoate, cetyl acetate, cetyl dimethicone, cetyl ethylhexanoate, cetyllactate, cetyl myristate, cetyl octanoate, cetyl palmitate, cetylricinoleate, citronella oil, clary sage oil, clove oil, cocoglycerides,coconut oil, cod-liver oil, corn oil, cotton oil, cottonseed oil,cyclohexasiloxane, cyclomethicone, Cyclomethicone 5-NF(cyclopentasiloxane), cyclotetrasiloxane, cypress oil, decyl oleate,diethyleneglycol diethylhexanoate, diethyleneglycol diisononanoate,diethyleneglycol dioctanoate, diethylhexanoate, diethylhexyl adipate,diethylhexyl malate, diethylhexyl succinate, diisopropyl adipate,diisopropyl dimerate, diisopropyl sebacate, diisosteary dimerdilinoleate, diisostearyl fumerate, dimethicone, dimethyl polysiloxane,dioctyl malate, dioctyl sebacate, disopropyl adipate, dodecyl oleate,Dow Corning 244 Fluid (cyclotetrasiloxane), Dow corning 246 Fluid(d6+d5) (cyclohexasiloxane & cyclopentasiloxane), epoxy-modifiedsilicone oil, essential oils, ester derivatives of lanolic acid, esteroils, ethylhexyl cocoate, ethylhexyl ethylhexanoate, ethylhexylhydroxystarate, ethylhexyl isononanoate, ethylhexyl palmitate,ethylhexyl palmytate, ethylhexyl pelargonate, ethylhexyl stearate,evening primrose oil, fatty acid-modified silicone oil, flaxseed oil,fluoro group-modified silicone oil, frankincense oil, gelled mineraloil, ginger oil, glycereth triacetate, glycerol triheptanoate, glyceryloleate, glyceryl trioctanoate, glyceryl triundecanoate, grape seed oil,grapefruit oil, groundnut oil, hard fat, hazelnut oil, heavy mineraloil, hempseed oil, herring oil, hexadecyl stearate, hexyl laurate,hydrocarbon oils, hydrogenated castor oil, hyssop oil, isoamyl laurate,isocetearyl octanoate, isocetyl isocetyl behenate, isocetyl lanolate,isocetyl palmitate, isocetyl salicylate, isocetyl stearate, isocetylstearoyl stearate, isodecyl ethylhexanoate, isodecyl isononanoate,isodecyl oleate, isododecane, isohexadecane isododecane, isohexadecanol,isohexyl decanoate, isononyl isononanoate, isononyl octanoate,isoparaffin, isopropyl isostearate, isopropyl lanolate, isopropyllaurate, isopropyl myristate, isopropyl palmitate, isopropyl stearate,isosteary citrate, isosteary salicylate, isosteary tartarate, isostearylbehenate, isostearyl erucate, isostearyl glycolate, isostearylisononanoate, isostearyl isostearate, isostearyl lactate, isostearyllinoleate, isostearyl linolenate, isostearyl malate, isostearylneopentanoate, isostearyl palmitate, isotridecyl isononanoate, jasmineoil, jojoba oil, lauryl lactate, lavender oil, lemon oil, light mineraloil, liquid paraffin, liquid triglycerides, lucerne oil, maize germ oil,maleated soybean oil, mandarin oil, manuka oil, marjoram oil, marrowoil, MCT oil, methylphenylpolysiloxane, millet oil, mineral oil,myristyl lactate, myristyl myristate, myristyl neopentanoate, myristylpropionate, myrrh oil, neopentylglycol dicaprate, neopentylglycoldicaprylate/dicaprate, neroli oil, nutmeg oil, octyl palmitate, octylstearate, octyldodecanol, octyldodecyl behenate, octyldodecylhydroxystearate, octyldodecyl myristate, octyldodecyl stearoyl stearate,oils from animal origin, oils of plant origin, oleyl erucate, oleyllactate, oleyl oleate, olive oil, or dimethiconol, palm oil,passionflower oil, peanut oil, PEG/PPG 18/18 dimethicone,pentaerythrityl tetrastearate, petitgrain oil, petrolatum, phenyltrimethicone, phenyltrimethicone,poly(dimethylsiloxane)-(diphenyl-siloxane) copolymer, polyalkylsiloxane, polyalkylaryl siloxane, polyalphaolefin, polyaryl siloxane,polyaryl siloxanes, polyether group-modified silicone oilcyclomethicone, polyether siloxane copolymer, polyether siloxanecopolymers, polyisobutylene, polyolefin, poppy oil, PPG alkyl ethers,PPG-10 cetyl ether, PPG-10 oleyl ether, PPG-11 stearyl ether, PPG-12butyl ether, PPG-14 butyl ether, PPG-15 butyl ether, PPG-15 stearylether, PPG-16 butyl ether, PPG-17 butyl ether, PPG-18 butyl ether, PPG-2butyl ether, PPG-2 methyl ether, PPG-20 butyl ether, PPG-20 oleyl ether,PPG-22 butyl ether, PPG-23 oleyl ether, PPG-24 butyl ether, PPG-26 butylether, PPG-28 cetyl ether, PPG-3 methyl ether, PPG-3 myristyl ether,PPG-30 butyl ether, PPG-30 cetyl ether, PPG-30 isocetyl ether, PPG-30oleyl ether, PPG-33 butyl ether, PPG-37 oleyl ether, PPG-4 butyl ether,PPG-4 lauryl ether, PPG-4 myristyl ether, PPG-40 butyl ether, PPG-5butyl ether, PPG-50 cetyl ether, PPG-50 oleyl ether, PPG-52 butyl ether,PPG-53 butyl ether, PPG-7 lauryl ether, PPG-9 butyl ether, PPG-9-13butyl ether, propyl myristate, propylene glycol dicaprate, propyleneglycol dicaprylate, propylene glycol myristyl ether acetate, propyleneglycol ricinoleate, rapeseed oil, rosehip oil, rye oil, safflower oil,sage oil, salmon oil, sesame oil, silicone oil, soya oil, soybean oil,stearyl caprate, stearyl dimethicone, stearyl heptanoate, stearylpropionate, sunflower oil, sweet almond oil, synthetic isoalkane,sysymbrium oil, syzigium aromaticum oil, tangerine oil, tea tree oil,therapeutic oils, tocopheryl acetate, tocopheryl linoleate, tridecylethylhexanoate, tridecyl isononanoate, triisocetyl citrate, unsaturatedor polyunsaturated oils, vanilla oil, verbena oil, walnut oil, wheatgerm glycerides, wheat germ oil, white petrolatum and mixtures thereof.

In one or more embodiments there is provided a composition comprising apetrolatum or a paraffin.

In one or more embodiments there is provided a composition in which thefatty alcohol has 14 or more carbons in their carbon chain; the fattyacid has 16 or more carbons in their carbon chain; the beeswax extractincludes a mixture of fatty alcohols, a majority of which has at least20 carbon atoms in their carbon chain, a fatty acid substituted with ahydroxyl group, cetyl alcohol, stearyl alcohol, arachidyl alcohol,behenyl alcohol, 1-triacontanol, hexadecanoic acid, stearic acid,arachidic acid, behenic acid; octacosanoic acid, 12-hydroxy stearic acidand/or mixtures thereof.

In one or more embodiments there is provided a composition in which theviscosity modifier and the active agent act synergistically to increasethe viscosity.

In one or more embodiments there is provided a composition which is afoamable composition and the carrier comprises:

a) about 60% to about 95% by weight of a hydrophobic solvent;

b) an oleaginous foamer complex comprising:

-   -   (1) about 0.1% to about 20% by weight of a fatty alcohol; and    -   (2) about 0.1% to about 20% by weight of a fatty acid and/or a        wax;    -   c) a liquefied or compressed gas propellant;        wherein the percent by weight is based on weight foamable        composition; wherein the ratio of composition other than        propellant to propellant is from about 100:1 to about 100:30;        and wherein upon dispensing the foamable carrier composition        forms a breakable foam that is stable, yet breaks easily upon        application of shear force.

In one or more embodiments there is provided a foamable composition inwhich the foam produced from the foamable composition has an averagebubble size of less than about 300 microns of less, or less than about200 microns, or less than about 150 microns.

In one or more embodiments there is provided a composition in which thecomposition further comprises at least one additional therapeutic agentselected from the group consisting of an antibiotic agent, a steroidalanti-inflammatory agent, an immunosuppressive agent, an immunomodulator,an immunoregulating agent, a hormonal agent, an androgen, an estrogen, aprostaglandin, an antiandrogen agent, a testosterone inhibitor, adihydrotestosterone inhibitor, antibacterial agent, an antifungal agent,an antiviral agent, an antiparasitic agent, antimicrobial, a retinoid,vitamin A, a vitamin A derivative, vitamin B, a vitamin B derivative,vitamin C, a vitamin C derivative, vitamin D, a vitamin D derivative,vitamin E, a vitamin E derivative, vitamin F, a vitamin F derivative,vitamin K, a vitamin K derivative, a wound healing agent, adisinfectant, an anesthetic, an antiallergic agent, a keratolytic agent,urea, a urea derivative, an alpha hydroxyl acid, lactic acid, glycolicacid, a beta-hydroxy acid, a protein, a peptide, a neuropeptide, anallergen, an immunogenic substance, a haptene, an oxidizing agent, anantioxidant, a dicarboxylic acid, azelaic acid, sebacic acid, adipicacid, fumaric acid, a retinoid, an antiproliferative agent, ananticancer agent, a photodynamic therapy agent, benzoyl chloride,calcium hypochlorite, magnesium hypochlorite, an anti-wrinkle agent, aradical scavenger, a metal, silver, a metal oxide, titanium dioxide,zinc oxide, zirconium oxide, iron oxide, silicone oxide, anorgano-metallic compound, and organo-boron compound, an organo-berylliumcompound, an tellurium compound, talc, carbon, an anti wrinkle agent, askin whitening agent, a skin protective agent, a masking agent, ananti-wart agent, a refatting agent, a lubricating agent and mixturesthereof.

In one or more embodiments there is provided a composition furthercomprising a surfactant.

In one or more embodiments there is provided a composition furthercomprising about 1% to about 25% by weight of a polar solvent or apenetration enhancer.

In one or more embodiments there is provided a composition in which thepolar solvent is selected from polyols, glycerol (glycerin), propyleneglycol, hexylene glycol, diethylene glycol, propylene glycol n-alkanols,terpenes, di-terpenes, tri-terpenes, terpen-ols, limonene, terpene-ol,1-menthol, dioxolane, ethylene glycol, other glycols, sulfoxides,dimethylsulfoxide (DMSO), dimethylformanide, methyl dodecyl sulfoxide,dimethylacetamide, monooleate of ethoxylated glycerides (with 8 to 10ethylene oxide units), azone (1-dodecylazacycloheptan-2-one),2-(n-nonyl)-1,3-dioxolane, esters, isopropyl myristate/palmitate, ethylacetate, butyl acetate, methyl proprionate, capric/caprylictriglycerides, octylmyristate, dodecyl-myristate, myristyl alcohol,lauryl alcohol, lauric acid, lauryl lactate ketones, amides, acetamideoleates, triolein; various alkanoic acids, caprylic acid, lactamcompounds, azone; alkanols, dialkylamino acetates, and admixturesthereof; or from polyethylene glycol (PEG), PEG200 (MW (molecularweight) about 190-210 kD), PEG300 (MW about 285-315 kD), PEG400 (MWabout 380-420 kD), PEG600 (MW about 570-630 kD), PEG 4000, PEG 6000, PEG10000 and mixtures thereof.

In one or more embodiments there is provided a composition in which thepenetration enhancer is selected from the group consisting of propyleneglycol, butylene glycol, hexylene glycol, glycerol, pentaerythritol,sorbitol, mannitol, oligosaccharides, dimethyl isosorbide, monooleate ofethoxylated glycerides having about 8 to 10 ethylene oxide units,polyethylene glycol 200-600, transcutol, glycofurol and a cyclodextrin.

In one or more embodiments there is provided a composition in which theactive agent is benzoyl peroxide.

In one or more embodiments there is provided a method for controllingformulation viscosity by selecting appropriate concentrations of a waxor fatty alcohol or fatty acid or a combination thereof and an activeagent where the viscosity of the formulation can be increased, orstabilized by the addition of the active agent

In one or more embodiments there is provided a method of preventing ortreating or alleviating a disease or disorder, the method comprisingadministering any of the preceding compositions topically to a subjecthaving or anticipated to have a disease or a disorder in need oftreatment.

In one or more embodiments there is provided a method for intradermaldelivery of the active agent into the skin with minimal or negligibletransdermal delivery. In one or more alternative embodiments aformulation is provided to achieve intra mucosal delivery. In certainembodiments the composition provides for transdermal delivery. In one ormore embodiments the composition can be used for prevention of a diseaseor disorder. The composition or foam is applied to a target surface orarea in or on which prevention is sought. In other embodiments thecomposition or foam is used to treat or ameliorate a disease ordisorder. In still further embodiments it may be used to provide aperiod of remission from the disease or disorder.

In one or more embodiments the composition is used for treating eyeinfections. In one or more embodiments the drug carrier is formulatedfor use on sensitive target areas such as sensitive or damaged skinareas, wounds, burns, mucosal membranes, body cavities and the eye. Inone or more embodiments the composition is intended for use in treatmentor prevention of eye infections. For sensitive use, hydrophobic solventsthat are suitable for ophthalmic targets or for use in wounds or burnsand are compatible with the active pharmaceutical ingredients areidentified.

BRIEF DESCRIPTION OF THE DRAWINGS

The following figures are provided for the purpose of illustration onlyand are not intended to be limiting.

FIG. 1 is a graph of the percentage of change in formulation viscosityby addition of 0.1% Minocycline HCl as a function of placebo viscosity.

FIG. 2 is photographs of vials in horizontal and vertical positioncontaining formulation 016 without active ingredient (left vial) andwith 0.1% Minocycline HCl (right vial).

DETAILED DESCRIPTION

The gist of the present invention is based on the striking discoverythat the addition of a low concentration of an suspended active agentinto a composition or formulation comprising a oleaginous carriercomprising a hydrophobic solvent together with a second rheologymodulator which may be a fatty acid and/or a fatty alcohol and/or a waxdramatically modulates the rheological properties of the composition andin particular can synergistically change the level of viscosity of acomposition.

In one or more embodiments there is provided a composition orformulation for use as a vehicle or carrier comprising, a first rheologymodulator comprising an suspended active agent in an amount necessary tomodify controllably different rheological properties of the composition,a second rheology modulator comprising a second rheology modulator in anamount necessary to modify controllably the different rheologicalproperties of the composition and a carrier.

In one or more embodiments there is provided a composition orformulation for use as a vehicle or carrier comprising a first rheologymodulator comprising an suspended active agent in an amount necessary tomodify controllably the different rheological properties of thecomposition, a second rheology modulator in an amount necessary tomodify controllably the different rheological properties of thecomposition and an oleaginous carrier wherein adding a first modulatorto an oleaginous carrier results in no significant or substantial changeto the rheology as reflected in the viscosity of the composition;however further adding a second modulator to the compositionunexpectedly results in a synergistic effect on the rheology asreflected in the viscosity of the composition. Alternatively firstadding a second modulator to an oleaginous carrier results in anexpected increase in the viscosity of the composition, however thenfurther adding a first modulator to the composition surprisingly resultsin an unexpected synergistic effect on the viscosity of the composition.However, such synergistic affect is observed wherein the viscosity ofthe carrier or composition is less than about 25,000 centipoises (cPs)at room temperature prior to the addition of the first rheologymodulator.

In one or more embodiments there is provided a composition as a carrieror vehicle in which a therapeutic rheology modulator or complex thereofis incorporated therein and in which the therapeutic agent is chemicallystable and the formulation is physically stable and the therapeuticproperties of the agent are sustained or substantially so.

In one or more embodiments there is provided a composition as a vehicleor carrier in which a therapeutic rheology modulator or complex thereofis incorporated therein and which further includes a surfactant and inwhich the active pharmaceutical agent is chemically stable and theformulation is physically stable and the therapeutic properties of theagent are sustained or substantially so.

In one or more embodiments there is provided a composition as a vehicleor carrier in which a therapeutic rheology modulator or complex thereofis incorporated therein which further includes one or more othertherapeutic agents and in which the active pharmaceutical agent ischemically stable and the formulation is physically stable and thetherapeutic properties of the agent are sustained or substantially so.

In one or more embodiments there is provided a composition as a vehicleor carrier comprising a therapeutic rheology modulator or complexthereof in a waterless or non aqueous environment and in which theactive pharmaceutical agent is chemically stable and the formulation isphysically stable and the therapeutic properties of the agent aresustained or substantially so.

In one or more embodiments there is provided a composition as a vehicleor carrier comprising a therapeutic rheology modulator or complexthereof in a substantially waterless or non aqueous environment and inwhich the active pharmaceutical agent is chemically stable and theformulation is physically stable and the therapeutic properties of theagent are sustained or substantially so.

In an embodiment or more embodiments there is provided a composition asa vehicle or carrier comprising a therapeutic rheology modulator orcomplex thereof in a substantially waterless or non aqueous environment,where the therapeutic agent has low or minimal susceptibility to waterand can withstand up to about 10% water and more preferably up to about5% water and in which the active pharmaceutical agent is chemicallystable and the formulation is physically stable and the therapeuticproperties of the agent are sustained or substantially so.

In an embodiment or more embodiments there is provided a composition asa vehicle or carrier comprising a therapeutic rheology modulator orcomplex thereof, where addition of low concentrations of the activeagent has a strong and sometimes synergistic impact on the rheology ofthe composition and in which the active pharmaceutical agent ischemically stable and the formulation is physically stable and thetherapeutic properties of the agent are sustained or substantially so.

In an embodiment or more embodiments there is provided a composition asa vehicle or carrier comprising a therapeutic rheology modulator orcomplex thereof, where addition of low concentrations of saidtherapeutic agent has a synergistic and dramatic impact on rheologicalproperties of the composition for example the viscosity of thecomposition and in which the active pharmaceutical agent is chemicallystable and the formulation is physically stable and the therapeuticproperties of the agent are sustained or substantially so.

In an embodiment or more embodiments the therapeutic rheology modulatoror the therapeutic agent has a low concentration of less than about 1%;or less than about 0.5%; or less than about 0.1%; or less than about0.01%. In one or more other embodiments the therapeutic rheologymodulator or the therapeutic agent has a medium concentration of lessthan about 10%; or less than about 5%; or less than about 3%; or lessthan about 2%. In one or more other embodiments the therapeutic rheologymodulator or the therapeutic agent has a high concentration of less thanabout 30%; or less than about 25%; or less than about 20%; or less thanabout 15%. In one or more embodiments the concentration range oftherapeutic rheology modulator or the therapeutic agent is between about0.001% and about 0.1%; or is between about 0.01% and about 1%; or isbetween about 1% and about 10%; or is between about 10% and about 30%;or is between any two ranges, such as, between about 0.01% and about30%.

In an embodiment or more embodiments there is provided a composition asa vehicle or carrier wherein the active agent is selected from a listcomprising an antibiotic agent, a steroidal anti-inflammatory agent, animmunosuppressive agent, an immunomodulator, an immunoregulating agent,a hormonal agent, an androgen, an estrogen, a prostaglandin, anantiandrogen agent, a testosterone inhibitor, a dihydrotestosteroneinhibitor, antibacterial agent, an antifungal agent, an antiviral agent,an antiparasitic agent, an antimicrobial agent a retinoid, vitamin A, avitamin A derivative, vitamin B, a vitamin B derivative, vitamin C, avitamin C derivative, vitamin D, a vitamin D derivative, vitamin E, avitamin E derivative, vitamin F, a vitamin F derivative, vitamin K, avitamin K derivative, a wound healing agent, a disinfectant, ananesthetic, an antiallergic agent, a keratolytic agent, urea, a ureaderivative, an alpha hydroxyl acid, lactic acid, glycolic acid, abeta-hydroxy acid, a protein, a peptide, a neuropeptide, an allergen, animmunogenic substance, a haptene, an oxidizing agent, an antioxidant, adicarboxylic acid, azelaic acid, sebacic acid, adipic acid, fumaricacid, a retinoid, an antiproliferative agent, an anticancer agent, aphotodynamic therapy agent, benzoyl chloride, calcium hypochlorite,magnesium hypochlorite, an anti-wrinkle agent, a radical scavenger, ametal, silver, a metal oxide, titanium dioxide, zinc oxide, zirconiumoxide, iron oxide, silicone oxide, an organo-metallic compound, andorgano-boron compound, an organo-beryllium compound, a telluriumcompound, talc, carbon, an anti wrinkle agent, a skin whitening agent, askin protective agent, a masking agent, an anti-wart agent, a refattingagent, a lubricating agent and mixtures thereof.

In an embodiment or more embodiments there is provided a composition asa vehicle or carrier wherein active agent is a tetracycline.

In an embodiment or more embodiments there is provided a composition asa vehicle or carrier wherein the tetracycline is minocycline ordoxycycline.

In an embodiment or more embodiments there is provided a composition asa vehicle or carrier wherein active agent is selected from a listcomprising a cholesterol, mometasone furoate, doxycycline hyclate,salicylic acid, vitamin E, diclofenac, urea, terbinafine, permethrin,metronidazole, pimecrolimus benzoyl peroxide or salt thereof.

In one or more embodiments there is provided a composition as a vehicleor carrier wherein second rheology modulator is a fatty alcohol and/or afatty acid and/or a wax.

In one or more embodiments there is provided a solid or semi-solidcomposition or gel. In one or more embodiments the composition or gel isa liquid. Examples of a liquid gel include where a propellant is addedto the formulation (which prior to adding the propellant is a gel) orwhere the gel is loose or such that when subjected to gravity will pouror become liquid. In one or more embodiments the composition isthixotropic. In one or more embodiments when poured it displays flow butover time it reverts to being more viscous or gel like. In one or moreembodiments when shear force is applied it displays flow but over timereverts to being more viscous or gel like. In one or more embodiments asolid gel becomes flowable and later with time becomes solid or semisolid. In one or more embodiments a semi-solid gel becomes flowable andlater with time becomes solid or semi solid. In one or more embodimentsa liquid gel is flowable and later with time becomes solid or semisolid.

In one or more embodiments there is provided a composition as a vehicleor carrier wherein second rheology modulator is a solid or semi-solid ora liquid.

In one or more embodiments there is provided a foamable composition foruse as a vehicle or carrier in which therapeutic rheology modulator isstable or stabilized within foamable composition.

In one or more embodiments there is provided a method of preventing ortreating or alleviating a disease or disorder, the method comprisingadministering the composition topically to a subject having oranticipated to having a disease or a disorder in need of treatment. Inone or more embodiments the method of achieves a period of remission ofthe disease or disorder.

According to one or more embodiments, it is possible to make excellentlotions, creams, ointments, gels and foams from waterless orsubstantially waterless compositions. Such compositions containing firstand second rheology modulators as described herein are also idealcarriers for active pharmaceutical agents that are soluble in polarsolvents and which may be potentially unstable in an aqueousenvironment, for example, following a change in pH, or the introductiona metal catalyst or in the presence of an ionization or oxidation agent.

It has surprisingly been discovered that combinations of different typesand concentrations of active agents with different second rheologymodulators may result in modulations to the rheology of formulations inwhich the active pharmaceutical or cosmetic agent is chemically stableand furthermore, the formulation is physically stable as demonstratedherein in the Examples.

In one or more embodiments, the change in the formulation viscosity isrelated to the concentration of the active agent.

In one or more embodiments, the viscosity of the formulation isproportional to the concentration of the active agent: for example, thehigher the concentration of the active agent, the higher the formulationviscosity. In one or more embodiments the relationship is exponential.

In one or more embodiments, the viscosity increasing effect of theactive agent reaches a plateau when the concentration of the activeagent is increased. In certain other embodiments the viscositydecreasing effect of the active agent likewise reaches a plateau whenthe concentration of the active agent is increased.

In one or more embodiments, the viscosity of the formulation containingthe active agent is more than about twice the viscosity of the sampleformulation is without the active agent, wherein the active agent ispresent at a concentration of less than about 10%, less than about 5%,less than about 1%, less than about 0.5%, less than about 0.1%, lessthan about 0.05%, or less than about 0.01%.

In one or more embodiments skin penetration of the active agent isimproved. In one or more embodiments the penetration is primarilyintradermal. In one or more embodiments there is little or notransdermal penetration. In one or more embodiments the active agent isconcentrated in the statum corneum. In one or more embodiments theactive agent is concentrated in the live skin layer. In one or moreembodiments the active agent is distributed throughout the skin.

Active agents had practically no effect on the viscosity of acomposition which did not comprise second rheology modulators. As shownin formulations of Example 2, mixtures of mineral oils or soybean oil orpetrolatum and C12-C15 alkyl benzoate had a low viscosity. After theaddition of a tetracycline such as Minocyclineminocycline HCl, theviscosity of the formulation remained practically unchanged and activeagents sediment.

Similarly, as shown in formulations of Example 3, it appears that informulations based on high amounts of semi-solid hydrophobic solvents,such as petrolatum or coconut oil, alone or in combination with fattyalcohols and/or fatty acids, the viscosity of the formulation remainedunchanged after the addition of 0.1% Minocyclineminocycline HCl.

It was therefore surprisingly observed that addition of lowconcentrations of an active agent had a synergistic and dramatic impacton the oleaginous composition viscosity as for example shown in Example4a. The addition of Minocyclineminocycline HCl to mineral oil-basedformulations led to a very substantial increase in viscosity, despitethe very low amount of Minocycline HCL used, namely 0.1%. These totallyunexpected results show that the combination of a tetracycline, even atvery low concentrations, with fatty alcohols, or fatty acids and/orwaxes (e.g. hydrogenated castor oil, with or without beeswax) had astrong synergistic effect on oleaginous formulation viscosity. Thiseffect was observed in compositions containing certain fatty alcoholssuch as myristyl alcohol or cetyl alcohol or stearyl alcohol.

It was found that adding a first modulator to an oleaginous carrierresulted in no significant or substantial change to the rheology asreflected in the viscosity of the composition; however further adding asecond modulator to the composition unexpectedly resulted in asynergistic effect on the rheology as reflected in the viscosity of thecomposition. Alternatively first adding a second modulator to anoleaginous carrier resulted in an expected increase in the viscosity ofthe composition, however then further adding a first modulator to thecomposition surprisingly resulted in an unexpected synergistic effect onthe viscosity of the composition. However such synergistic affect isobserved wherein the viscosity of the carrier or composition is lessthan about 25,000 centipoises (cPs), less than about 12,000 cPs, lessthan about cPs 8,000 cPs, or less than about 2,000 cPs at roomtemperature prior to the addition of the first rheology modulator.

Very surprisingly, as described in Example 4c it was discovered that theaddition of minocycline HCl to mineral oil-based formulations,containing as low as 5% of a fatty alcohol, or a fatty acid or a wax ora combination of a fatty alcohol and a wax, led to a very substantialincrease in viscosity, where the increase in viscosity is dependent onthe concentration of the active agent. It was noticed that formulationshaving a higher concentration of active agent had a higher viscosity. Sothere is a relationship between the amount of the active agent andresultant viscosity over a specific range of concentration typical foreach active ingredient.

It was further observed that the combination of a tetracycline with amixture of mineral oils, fatty alcohols, fatty acids and waxes had astrong synergistic effect and increased the formulation viscosity asshown in Example 4c. The viscosity of a formulation containing 0.50%minocycline HCl was about three times higher than the viscosity of theplacebo formulation. It was also evident that the effect on theformulation viscosity was directly related to the concentration of thetetracycline: the higher the tetracycline concentration, the higher theviscosity of the formulation.

It was further discovered that in formulations based on petrolatum andvarious amounts of mineral oil, the influence of the combination of atetracycline with fatty alcohols on formulation having initial highviscosity was minor. As shown in Example 5 when the viscosity of theplacebo formulation is high, and the concentration of minocyline is low(e.g. 0.1%) no significant increase in viscosity was noticed.Formulations which contained low amounts of mineral oil exhibited aminor increase in viscosity upon the addition of 0.1% minocycline HCl(which with higher amounts of minocycline could have been moresubstantial). However, very surprisingly, it was observed that theaddition of a very low amount of minocycline HCl greatly increasedformulation viscosity, when the viscosity of the placebo formulation waslow, which contained high amounts of mineral oil.

As shown in FIG. 1, the percentage of change in viscosity by theaddition of minocycline HCl appears to be exponentially related to theviscosity of the formulation placebo. As shown in FIG. 2, the additionof minocycline HCl to the oleaginous formulation based on mineral oilchanges the physical state of the formulation from a liquid to asemi-solid.

In one or more embodiments, the lower the viscosity of the placeboformulation, the greater the increase in formulation viscosity afteraddition of the active agent.

It was unexpectedly discovered that the combination of a tetracyclinewith a mixture of vegetable oils, fatty alcohols, fatty acids and waxeshad a strong synergistic effect and increased the formulation viscosity.The viscosity of a formulation containing about 1% minocycline HCl wasabout twice as high as the viscosity of the placebo formulation.Moreover, the effect on the formulation viscosity was directly relatedto the concentration of the tetracycline: the higher the tetracyclineconcentration, the higher the viscosity of the formulation.

In one or more embodiments, there is provided an oleaginous formulationcontaining vegetable oils and a tetracycline in synergistic combinationwith a fatty alcohol, a fatty acid and a wax, wherein the viscosity ofthe formulation is increased by the addition of the active ingredient bymore than about 20%, or by more than about 50%, or by more than about100%, or by more than about 200%, or by more than about 300%, or by morethan about 500%.

Tetracycline antibiotics are known to be very unstable active agentsthat are degraded by a wide range of commonly used pharmaceuticalexcipients. For example, it has been found that minocycline is degradedin a few days by different hydrophilic solvents (such as water,glycerin, sodium PCA, propylene glycol and polyethylene glycols), bywater dispersed polymers (such as xanthan gum, poloxamers, carbomers,methocel, sodium carboxymethylcellulose) and by surfactants (such aspolysorbates, sorbitan esters, polyoxyalkyl esters and lanolin-basedsurfactants). Thus, the achievement of a long term stable formulation oftetracycline antibiotics provided a major challenge.

Surprisingly, and despite the known instability of tetracyclineantibiotics, the accelerated stability results of the formulation at 6months at 40° C. showed minimal degradation of the active agent in theformulations. The formulations showed an extended accelerated stabilityfor the tetracycline antibiotic active agent and an outstanding physicalstability, wherein the viscosity of the formulation is substantiallyincreased by the addition of the active agent.

In another experiment, a sample of formulation was stored during 6months at 40° C. and tested for active agent content uniformity andphysical stability. It was found that minocycline HCl was homogeneouslydispersed into formulation even after prolonged incubation at 40° C.Furthermore, it was found that the formulation remained as a homogeneousgel after 6 months of incubation at 40° C.

In one or more embodiments, there is provided a formulation wherein theactive agent is homogeneously dispersed in the formulation and remainshomogeneously dispersed after 3 weeks of incubation at 40° C., or at onemonth, or at two months, or at three months, or at four months, or atfive months, or at six months incubation at 40° C.

It was further discovered that the increase in viscosity wasdemonstrated in different mineral oil based formulations comprising afatty alcohol and other active ingredients. To a lesser extent, anincrease in formulation viscosity was observed with cholesterol which isalso a 4-ring compound and with benzoyl peroxide. It can be noted thatthe strongest effect was observed with tetracycline compounds, such asminocycline HCl and tetracycline HCl (which is another compound of thetetracycline class). Even at concentrations as low as 0.05%, theaddition of minocycline HCl to the formulations more than doubled theviscosity. Micronized preparations appear to have a more pronouncedeffect.

It was also unexpectedly discovered that viscosity increaseddramatically after the addition of a wide range of different activeingredients to a mineral oil based formulation containing a hydrogenatedcastor oil instead of fatty alcohol or fatty acid [See Example 8]. Thehydrogenated castor oil had a very strong synergistic effect withdifferent active ingredients for example 0.1% Minocyclineminocycline HClnon micronized, mometasone furoate, terbinafine, metronidazolepimecrolimus. The viscosity of a formulation containing 0.1%non-micronized minocycline HCl was more than about 5 times as high asthe viscosity of the formulation containing 0.1% micronized minocyclineHCl. This is in contrast to the results with fatty alcohol where higherviscosity was observed with micronized minocycline HCL.

It was unexpectedly found that the addition of minocycline HCl tomineral oil-based formulations containing different concentrations ofbeeswax alone led to changes in viscosity depending on the amount ofbeeswax, at low concentration of Minocycline HCL used. Without beingbound to any theory, one possibility may be that the addition of beeswaxto oils can build a some sort of netted framework. It may further beassumed that when about 5% of beeswax is included in the composition,the netted framework is relatively weak and is broken or destabilized bythe addition of Minocycline HCl, which may explain the decrease informulation viscosity. However, it may be assumed that when 10% beeswaxis included in the composition the netted framework is stronger and theaddition of low amounts of Minocycline HCl further strengthens saidnetted framework leading to an increase in formulation viscosity.

Thus according to one or more embodiments there is provided a method forcontrolling formulation viscosity by selecting appropriateconcentrations of a wax or fatty alcohol or fatty acid or a combinationthereof and an active ingredient where the viscosity of the formulationcan be increased, or stabilized by the addition of the activeingredient.

It was further discovered that tetracyclines like minocycline areincompatible with many surfactants, many hydrophilic solvents, an oil, aliquid branched fatty alcohol; a metal oxide and water. A detailed listof compatible substances and incompatible substances appears in Example10.

Rheological Properties of Semisolids

Manufacturers of pharmaceutical gels, ointments and cosmetic creams haverecognized the desirability of controlling their consistency. It mustspread evenly and smoothly in various climates yet adhere well to theaffected area without being tacky or difficult to remove.

Rheology of Gel Compositions and Gel Properties

Rigidity and viscosity are two separate rheological parameters used tocharacterize the mechanical properties of gels. Gel compositions shouldpreferably posses the following properties.

-   -   1. Uniformity: The composition should be formulated so that it        is and can remain uniform without separation or precipitation        over time. This property is of high importance when the product        is intended to be a pharmaceutical product.    -   2. Flowability: The composition, when placed in a tube or        container and expelled under shear force should be flowable.    -   3. Quality: Upon release from the tube or container, the        composition should generate a homogeneous gel. In one embodiment        the gel is thixotropic.    -   4. Stability/Breakability: The fine balance between stability        and breakability of the gel coming out of the tube or container        is very delicate: on the one hand the gel should preferably not        be very runny upon release from the tube or container and not        lose its thixotropy property as a result of exposure to skin        temperature; and on the other hand, it should be “breakable”,        i.e., it should spread easily, break down and absorb into the        skin or membrane upon application of mild shear force.    -   5. Skin Feeling: To ensure patient compliance the skin feeling        after application should be pleasant, and greasy or waxy        residues should be minimal.    -   6. Non-irritating: The above requirements should be achieved        with the awareness that formulation excipients, especially        surfactants, can be irritating, and should preferably be        eliminated from the composition or reduced as much as possible.    -   7. Delivery: The composition should also be designed to ensure        efficient delivery of a therapeutic agent into the target site        of treatment.    -   8. Compatibility: Finally, the first rheology modulating agent,        which is a pharmaceutical or cosmetic active agent should be        chemically compatible with the second viscosity modulating agent        and with the whole list of ingredients in the composition.

Foamable Composition and Foam Properties

The ability to achieve quality foam with a substantial concentration ofhydrophobic solvent without a surfactant is described in U.S.Provisional Application No. 61/248,144 filed Oct. 2, 2009 and titled“Surfactant-Free Water-Free Foamable Compositions, Breakable Foams AndTheir Uses,” and in U.S. Provisional Application No. 61/322,148 filedApr. 8, 2010 and titled “Surfactant-Free Water-Free FoamableCompositions, Breakable Foams And Gels And Their Uses.” This issurprising, because usually, such solvents are not prone to creating afoam. The challenge is not just to achieve a quality foam but also toattain a formulation that will satisfy a plurality of two, three, four,five, six or more of the following property specificationssimultaneously.

Notably, the pressurized composition is flowable and releases a foamfreely, even though it might be expected that such concentrations of afatty alcohol and fatty acid would make the hydrophobic solvent ‘gel’ or‘semi-solid.

-   -   1. Uniformity: The composition should be formulated so that it        is uniform and can remain uniform without phase separation or        precipitation over time. This property is of high importance        when the product is intended to be a pharmaceutical product.    -   2. Flowability: The composition, when placed in an aerosol        container and pressurized should be flowable such that it can be        expelled through the canister valve. It should preferably also        be shakable inside the container. These requirements create a        formulation challenge, because low or non-viscous flowable and        shakable compositions are prone to undergo phase separation or        precipitation.    -   3. Quality: Upon release from the can, the composition should        generate a foam of good or excellent quality having low density        and small bubble size.    -   4. Stability/Breakability: The fine balance between stability        and breakability of the foam coming out of the container is very        delicate: on one hand the foam should preferable not be “quick        breaking”, i.e., it should be at least short term stable upon        release from the pressurized container and not break as a result        of exposure to skin temperature; and on the other hand, it        should be “breakable”, i.e., it should spread easily, break down        and absorb into the skin or membrane upon application of mild        shear force.    -   5. Skin Feeling: To ensure patient compliance the skin feeling        after application should be pleasant, and greasy or waxy        residues should be minimal.    -   6. Non-irritating: The above requirements should be achieved        with the awareness that formulation excipients, especially        surfactants, can be irritating, and should preferably be        eliminated from the composition or reduced as much as possible.    -   7. Delivery: Finally, the composition should also be designed to        ensure efficient delivery of a therapeutic agent into the target        site of treatment.

Based on extensive investigations and trial and error experiments, ithas been found that such properties can be achieved for formulations asdisclosed in U.S. Provisional Application No. 61/248,144 filed Oct. 2,2009 and titled “Surfactant-Free Water-Free Foamable Compositions,Breakable Foams And Their Uses,” and in U.S. Provisional Application No.61/322,148 filed Apr. 8, 2010 and titled “Surfactant-Free Water-FreeFoamable Compositions, Breakable Foams And Gels And Their Uses,” andwhich are further advantageous because of the ability of hydrophobicsolvents to dissolve or suspend certain active agents while providing anenvironment for the active agent which assists in preventing theirdegradation.

Compositions

All % values are provided on a weight (w/w) basis.

In one or more embodiments where ever a phrase is used to refer to aconcentration of above X % or below X % it can also include X % or ofabove about X % or below about X % it can also include about X %.

In one or more embodiments the term “about” has its usual meaning in thecontext of pharmaceutical and cosmetic formulations to allow forreasonable variations in amounts that can achieve the same effect. Inone or more embodiments about can encompass a range of plus and minus20%. In one or more embodiments about can encompass a range of plus andminus 10%.

In one or more embodiments there is provided a composition for cosmeticor pharmaceutical application comprising:

-   -   a) a first rheology modulator comprising a suspended active        agent    -   b) a second rheology modulator selected from the list of (i) at        least one at least one fatty alcohol, (ii) at least one fatty        acid, (iii) at least one wax; and mixtures thereof; and    -   c) a carrier,    -   wherein the suspended active agent is a pharmaceutical or        cosmetic suspended active agent;    -   wherein the rheology of the composition after addition of the        first modulator and second modulator to the carrier is better        than the rheology of the composition after the addition of the        second modulator to the carrier without the first modulator and        is better than the rheology of the composition after the        addition of the first modulator to the carrier without the        second modulator.

In certain embodiments, the viscosity of the carrier or compositionwithout the addition of the first rheology modulator is less than about25,000 centipoises (cPs) at room temperature.

In one or more embodiments the composition forms a gel. The gel may be aliquid gel, a semi-solid gel or a solid gel. The gel may further be anair gel, hydro gel or an oleaginous (organo) gel.

In one or more embodiments a liquefied or compressed gas propellant isadded to the composition according to the different embodimentsmentioned above thereby transforming the gel into a foamablecomposition. Upon release from an aerosol container, the foamablecomposition forms an expanded foam suitable for topical administration.In one or more embodiments the foamable composition is either abreakable or quickly breaking foam. In one or more embodiments thefoamable composition is substantially surfactant free. In one or moreother embodiments it is essentially free of any surfactants.

In one or more embodiments oily emollients are added to the compositionto provide or improve a pleasant skin feeling, and/or lubricating effectwith reduced friction. In one or more embodiments volatile silicones areadded to reduce greasy feeling. In one or more embodiments waxes areadded to improve rheology or stabilize the composition's gels orstructure.

In an embodiment, the wax can be a liquid wax, a solid wax, an animalwax, a vegetable wax, a mineral wax, a natural wax or a synthetic wax.In an embodiment the wax is selected from a list comprising paraffinwax, beeswax, hydrogenated castor oil or mixtures thereof. In anembodiment the wax is a polyolefin. In one or more embodiments there isprovided a composition comprising a paraffin wax. In one or moreembodiments the paraffin wax can have a melting point form about 37° C.In one or more embodiments the paraffin wax comprises of alkane chainsof between about C₂₀H₄₂ to C₄₀H₈₂. In one or more embodiments the chainsare substantially straight chain. In some embodiments branched orunsaturated molecules can be present. Branched chains are sometimesreferred to as isoparaffins. In one or more embodiments the paraffin waxcan be selected from the group consisting of paraffin wax 58-62° C.,paraffin wax 51-53° C., and paraffin wax 42-44° C., or mixtures thereof.In one or more other embodiments other melting point ranges can beselected such as 125° F. to 135° F.; 127° F. to 130° F.; 130° F. to 135°F.; 135° F. to 145° F.; 140° F. to 145° F.; 150° F. to 155° F.; 150° F.to 165° F.; 160° F. to 165° F.; or such as 43-46° C.; 46-53° C.; 48-50°C.; 52-54° C.; 53-55° C.; 54-57° C.; 54-58° C.; 58-60° C.; 59-61° C.;60-62° C.; 62-66° C.; 65-68° C.; or any other similar or relativerange(s) or mixtures thereof. In an embodiment the wax is fully refined.In an embodiment it is suitable for cosmetic use. In an embodiment it issuitable for pharmaceutical use. In an embodiment the paraffin wax issoft.

In one or more embodiments antioxidants can be used to preventdegradation/oxidation, for example, butylated hydroxytoluene, which is afat soluble antioxidant.

According to one or more embodiments, the composition further comprisesone or more other cosmetic active agents or a pharmaceutical activeagents (severally and interchangeably termed herein “active agent”)which may or may not have a rheology modulating effect.

Surfactants play a role in foam formation and induce foam stability. Inone or more embodiments the formulation is substantially free ofsurfactants. In one or more other embodiments it is essentially free ofany surfactants. In one or more alternative embodiments a small amountof surfactant may be added preferably less than 1%. In one or moreembodiments foam adjuvants (e.g. fatty alcohols and fatty acids) andadditives (such as SiO2 which acts as a thickener and can providethixotropy) are added to improve rheology or stabilize foam structure oras a protective agent.

In one or more embodiments the composition is a foamable composition andcomprises propellant. Upon release from an aerosol container, thefoamable composition forms an expanded breakable foam suitable fortopical administration.

The composition is suitable for administration to various body areas,including, but not limited to the skin, a body surface, a body cavity, amucosal surface, e.g., the mucosa of the nose, mouth and eye, the ear,the respiratory system, the vagina or the rectum (severally andinterchangeably termed herein “target site”).

In one or more embodiments, the composition is waterless. By waterlessis meant that the composition contains no or substantially no, free orunassociated or absorbed water. It will be understood by a person of theart that to the extent the waterless solvents and substances misciblewith them of the present disclosure are hydrophilic, they can containwater in an associated or unfree or absorbed form and may absorb waterfrom the atmosphere.

In one or more embodiments the carrier comprises an activepharmaceutical or cosmetic agent which degrades in the presence ofwater, and in such cases the presence of water in the composition isclearly not desirable. Thus, in certain preferred embodiments, thecomposition is waterless. In other embodiments the active agent maytolerate the presence of a small amount of water and the waterlesscomposition is substantially non-aqueous. The term “substantiallynon-aqueous” is intended to indicate that the waterless composition haswater content preferably below about 2%, such as, below about 1.5%,below about 1%; or below about 0.5%.

In one or more embodiments, at least a portion of the therapeutic agentis suspended or dissolved evenly throughout the entire composition. Inone or more other embodiments the first rheology modulator is a solubleactive agent. For example when hydrogenated caster oil in mineral oil ischallenged with cholesterol the viscosity increases by about 200%. Incertain embodiments two or more first rheology modulators may be used incombination. Such combinations can be of two or more solid agents, or ofone or more solid agents (insoluble or partially soluble) and one ormore soluble agents or two or more soluble agents.

It has been discovered that formulations containing high amount of ahydrophobic solvents (such as mineral oil) are not prone to highviscosity or foaming. Surprisingly, it has been discovered that thecombination of a rheology modulating active agent and/or a fatty alcoholand/or fatty acid and/or a wax has viscosity and foam boostingproperties and provides gels and foams of good quality. It has beendiscovered that when rheology modulating active agents are added tofatty alcohols and/or fatty acids, for example, with a saturated carbonchain of between 14 to 22 carbons it can cause a rheology effect, suchas, a synergistic viscosity effect resulting in composition havingoutstanding viscosity properties Furthermore, the formulations of thepresent invention can provide foams of good quality in the presence ofvarious active ingredients with or without surfactants.

In one or more embodiments, the active agent is vitamin D or aderivative or analog thereof.

In one or more embodiments, the active agent is calcipotriol.

In one or more embodiments, the active agent is calcitriol.

In one or more embodiments, the active agent is selected from a listcomprising a tetracycline, cholesterol, mometasone furoate, doxycyclinehyclate, salicylic acid, vitamin E, diclofenac, urea, terbinafine,permethrin, metronidazole, pimecrolimus, benzoyl peroxide or saltthereof.

In one or more embodiments, the tetracycline is minocycline ordoxycycline or tetracycline.

In one or more embodiments, the composition is essentially free ofpolyols.

In one or more embodiments there is provided a surfactant freecomposition that is also free of short chain alcohols and/or polyol freeand/or polymeric free.

In one or more embodiments, composition is capable of providingintradermal delivery of the active agent into the skin with minimal ornegligible transdermal delivery.

In one or more embodiments, the composition has some preservativeefficacy.

In one or more embodiments, the composition is for use in eyeinfections.

In one or more embodiments, the composition is physically and chemicallystable for at least two months.

In one or more embodiments, the composition is physically and chemicallystable for at least three months.

In one or more embodiments, the composition is physically and chemicallystable for at least six months.

Hydrophobic Solvent

In an embodiment, the composition of the present invention comprises atleast one hydrophobic organic solvent. A “hydrophobic organic solvent”(also termed “hydrophobic solvent”) as used herein refers to a materialhaving solubility in distilled water at ambient temperature of less thanabout 1 gm per 100 mL, more preferably less than about 0.5 gm per 100mL, and most preferably less than about 0.1 gm per 100 mL. It is liquidat ambient temperature. The identification of a “hydrophobic solvent”,as used herein, is not intended to characterize the solubilizationcapabilities of the solvent for any specific active agent or any othercomponent of the foamable composition. Rather, such term is provided toaid in the identification of materials suitable for use as a hydrophobicsolvent in the compositions described herein.

In one or more embodiments the hydrophobic solvent is present at aconcentration of about 60% to about 95% or about 65% to about 90%; orabout 70% to about 90% or about 75% to about 85%.

In one or more embodiments, the composition of the present inventioncomprises at least one hydrophobic solvent, selected from the groupconsisting of a mineral oil, a hydrocarbon oil, an ester oil, atriglyceride oil, an oil of plant origin, an oil from animal origin, anunsaturated or polyunsaturated oil, a diglyceride, a PPG alkyl ether anda silicone oil.

As exemplified herein, members of each of the above listed groups ofhydrophobic solvents have been found to be compatible with hydrophobictetracyclines, such as minocycline and doxycycline.

Non-limiting examples of hydrocarbon oils include mineral oil, liquidparaffin, an isoparaffin, a polyalphaolefin, a polyolefin,polyisobutylene, a synthetic isoalkane, isohexadecane and isododecane.

Non-limiting examples of ester oils include alkyl benzoate, alkyloctanoate, C12-C15 alkyl benzoate, C12-C15 alkyl octanoate, arachidylbehenate, arachidyl propionate, benzyl laurate, benzyl myristate, benzylpalmitate, bis (octyldodecyl stearoyl) dimer dilinoleate, butylmyristate, butyl stearate, cetearyl ethylhexanoate, cetearylisononanoate, cetyl acetate, cetyl ethylhexanoate, cetyl lactate, cetylmyristate, cetyl octanoate, cetyl palmitate, cetyl ricinoleate, decyloleate, diethyleneglycol diethylhexanoate, diethyleneglycol dioctanoate,diethyleneglycol diisononanoate, diethyleneglycol diisononanoate,diethylhexanoate, diethylhexyl adipate, diethylhexyl malate,diethylhexyl succinate, diisopropyl adipate, diisopropyl dimerate,diisopropyl sebacate, diisosteary dimer dilinoleate, diisostearylfumerate, dioctyl malate, dioctyl sebacate, dodecyl oleate, ethylhexylpalmitate, ester derivatives of lanolic acid, ethylhexyl cocoate,ethylhexyl ethylhexanoate, ethylhexyl hydroxystarate, ethylhexylisononanoate, ethylhexyl palmytate, ethylhexyl pelargonate, ethylhexylstearate, hexadecyl stearate, hexyl laurate, isoamyl laurate, isocetylisocetyl behenate, isocetyl lanolate, isocetyl palmitate, isocetylstearate, isocetyl salicylate, isocetyl stearate, isocetyl stearoylstearate, isocetearyl octanoate, isodecyl ethylhexanoate, isodecylisononanoate, isodecyl oleate, isononyl isononanoate, isodecyl oleate,isohexyl decanoate, isononyl octanoate, isopropyl isostearate, isopropyllanolate, isopropyl laurate, isopropyl myristate, isopropyl palmitate,isopropyl stearate, isostearyl behenate, isosteary citrate, isostearylerucate, isostearyl glycolate, isostearyl isononanoate, isostearylisostearate, isostearyl lactate, isostearyl linoleate, isostearyllinolenate, isostearyl malate, isostearyl neopentanoate, isostearylpalmitate, isosteary salicylate, isosteary tartarate, isotridecylisononanoate, isotridecyl isononanoate, lauryl lactate, myristyllactate, myristyl myristate, myristyl neopentanoate, myristylpropionate, octyldodecyl myristate, neopentylglycol dicaprate, octyldodecanol, octyl stearate, octyl palmitate, octyldodecyl behenate,octyldodecyl hydroxystearate, octyldodecyl myristate, octyldodecylstearoyl stearate, oleyl erucate, oleyl lactate, oleyl oleate, propylmyristate, propylene glycol myristyl ether acetate, propylene glycoldicaprate, propylene glycol dicaprylate, propylene glycol dicaprylate,maleated soybean oil, stearyl caprate, stearyl heptanoate, stearylpropionate, tocopheryl acetate, tocopheryl linoleate, glyceryl oleate,tridecyl ethylhexanoate, tridecyl isononanoate and triisocetyl citrate.

Non-limiting examples of triglycerides and oils of plant origin includealexandria laurel tree oil, avocado oil, apricot stone oil, barley oil,borage seed oil, calendula oil, canelle nut tree oil, canola oil,caprylic/capric triglyceride castor oil, coconut oil, corn oil, cottonoil, cottonseed oil, evening primrose oil, flaxseed oil, groundnut oil,hazelnut oil, glycereth triacetate, glycerol triheptanoate, glyceryltrioctanoate, glyceryl triundecanoate, hempseed oil, jojoba oil, lucerneoil, maize germ oil, marrow oil, millet oil, neopentylglycoldicaprylate/dicaprate, olive oil, palm oil, passionflower oil,pentaerythrityl tetrastearate, poppy oil, propylene glycol ricinoleate,rapeseed oil, rye oil, safflower oil, sesame oil, shea butter, soya oil,soybean oil, sweet almond oil, sunflower oil, sysymbrium oil, syzigiumaromaticum oil, tea tree oil, walnut oil, wheat germ glycerides andwheat germ oil.

Non-limiting examples of PPG alkyl ethers include PPG-2 butyl ether,PPG-4 butyl ether, PPG-5 butyl ether, PPG-9 butyl ether, PPG-12 butylether, PPG-14 butyl ether, PPG-15 butyl ether, PPG-15 stearyl ether,PPG-16 butyl ether, PPG-17 butyl ether, PPG-18 butyl ether, PPG-20 butylether, PPG-22 butyl ether, PPG-24 butyl ether, PPG-26 butyl ether,PPG-30 butyl ether, PPG-33 butyl ether, PPG-40 butyl ether, PPG-52 butylether, PPG-53 butyl ether, PPG-10 cetyl ether, PPG-28 cetyl ether,PPG-30 cetyl ether, PPG-50 cetyl ether, PPG-30 isocetyl ether, PPG-4lauryl ether, PPG-7 lauryl ether, PPG-2 methyl ether, PPG-3 methylether, PPG-3 myristyl ether, PPG-4 myristyl ether, PPG-10 oleyl ether,PPG-20 oleyl ether, PPG-23 oleyl ether, PPG-30 oleyl ether, PPG-37 oleylether, PPG-40 butyl ether, PPG-50 oleyl ether and PPG-11 stearyl ether.Preferred PPG alkyl ethers according to the present invention includePPG-15 stearyl ether, PPG-2 butyl ether and PPG-9-13 butyl ether.

Non-limiting examples of oils from animal origin include herring oil,cod-liver oil and salmon oil.

The hydrophobic solvent may be an emollient, i.e., a hydrophobic liquidhaving a softening or soothing effect especially to the skin. In someembodiments the liquid oil may contain a solid or semi solid hydrophobicmatter at room temperature.

Essential oil, which is usually a concentrated, hydrophobic liquidcontaining volatile aroma compounds from plants usually conveyingcharacteristic fragrances. Non limiting examples include lavender,peppermint, and eucalyptus. A therapeutic oil is a hydrophobic liquidwhich is said to have a therapeutic effect or to have associated with itcertain healing properties. Therapeutic oils contain active biologicallyoccurring molecules and, upon topical application, exert a therapeuticeffect. Non limiting examples include manuka oil, rosehip oil, whichcontains retinoids and is known to reduce acne and post-acne scars, andtea tree oil, which possesses anti-microbial activity includingantibacterial, antifungal and antiviral properties as well as any othertherapeutically beneficial oil known in the art of herbal medication.Many essential oils, are considered “therapeutic oils.” Other nonlimiting examples of essential oils are basil, camphor, cardamom,carrot, citronella, clary sage, clove, cypress, frankincense, ginger,grapefruit, hyssop, jasmine, lavender, lemon, mandarin, marjoram, myrrh,neroli, nutmeg, petitgrain, sage, tangerine, vanilla and verbena,

Some embodiments include silicone oils. Non-limiting examples ofsilicone oils include a cyclomethicone, a dimethicone, a polyalkylsiloxane, a polyaryl siloxane, a polyalkylaryl siloxane, a polyethersiloxane copolymer, a poly(dimethylsiloxane)-(diphenyl-siloxane)copolymer, a dimethyl polysiloxane, an epoxy-modified silicone oil, afatty acid-modified silicone oil, a fluoro group-modified silicone oil,a methylphenylpolysiloxane, phenyl trimethicone and a polyethergroup-modified silicone oil. In some embodiments, the silicone oil iscyclomethicone, cyclotetrasiloxane, cyclohexasiloxane,phenyltrimethicone, Dow corning 246 Fluid (d6+d5) (cyclohexasiloxane &cyclopentasiloxane), Dow Corning 244 Fluid (cyclotetrasiloxane),Cyclomethicone 5-NF (cyclopentasiloxane), stearyl dimethicone,phenyltrimethicone, cetyl dimethicone, caprylyl methicone, PEG/PPG 18/18dimethicone, or dimethiconol.

In one or more embodiments, the hydrophobic solvent may be selected fromcyclomethicone; isopropyl myristate, PPG-15 stearyl ether;octyldodecanol; isohexadecanol, diisopropyl adipate; cetearyl octanoate;hydrogenated castor oil; MCT oil; heavy mineral oil; light mineral oil;coconut oil and soybean oil, castor oil, cocoglycerides, disopropyladipate, beeswax, isododecane, gelled mineral oil, white petrolatum,petrolatum, paraffin 51-53, calendula oil, shea butter, grape seed oil,almond oil, jojoba oil, avocado oil, peanut oil, and hard fat andcombination thereof.

Mixtures of two or more hydrophobic solvents in the same composition iscontemplated. Furthermore, in certain embodiments, the use of mixturesof two or more hydrophobic solvents is preferred.

Yet, in certain embodiments, the hydrophobic solvent is a mixture of oneor more liquid hydrophobic solvents, as listed above, which anadditional hydrophobic substance, which is not liquid (such aspetrolatum), provided that the mixture of all hydrophobic substances(excluding the oleaginous foamer complexes), is liquid at ambienttemperature. In an embodiment the resultant mixture upon includingpropellant is liquid at ambient temperature. For example petrolatum maybe added to provide a degree of occlusivity so that the formulation whenapplied to a skin surface can operate to increase skin moisture and/orreduced transdermal water loss. In certain other embodiments fluidity ofthe composition can be achieved by utilizing liquidizing solvents (e.g.C12 C15 Alkyl benzoate) and/or liquefied propellants and/or optionallyliquid adjuvants. Inclusion of higher amounts of propellant was founduseful in order to improve flowability of the formulation from thecanister or by using propellants having a higher vapor pressure.

Composition Components

The composition components comprise: a carrier, a first rheologymodulator and a second rheology modifier. The carrier can comprise, forexample a hydrophobic solvent. In one or more embodiments the carriercan comprise about 60% to about 95% by weight of the composition. Thefirst rheology modulator is a therapeutic rheology modulator. In one ormore embodiments it can comprise about 0.001% to about 30% by weight ofthe composition. The second rheology modulator comprises a fattyalcohol; a fatty acid; a wax and mixtures thereof. In one or moreembodiments it can comprising about 0.1% to about 20% by weight of afatty alcohol; and/or about 0.1% to about 20% by weight of a fatty acid;and/or a wax and a third member which is a active agent. In one or moreembodiments the carrier is present at a concentration of about 60% toabout 95% or about 65% to about 90%; or about 70% to about 90% or about75% to about 85%. In certain embodiments the amount of the secondrheology modulator comprises about 0.4% to about 18% by weight. Incertain embodiments the amount of the second modulator comprises about0.6% to about 12% by weight. In certain embodiments the amount of thesecond modulator comprises about 0.8% to about 10% by weight. In certainembodiments the amount of the second modulator comprises about 2% toabout 7% by weight. In certain other embodiments, the concentration ofthe second modulator can be within any one of the following ranges (i)between about 0.1% and about 1%, (ii) between about 1% and about 5%,(iii) between about 5% and about 10%, or (iv) between about 10% andabout 20%. In one or more embodiments, each member is at a concentrationat about 5% to about 10% by weight. In one or more embodiments theamount of the first modulator is present at a concentration of less thanabout 1%, or less than about 0.5%, or less than about 0.1%, or less thanabout 0.01%

Second Rheology Modulators

The second rheology modulator (waxes, fatty alcohols and fatty acids)may be solids semi-solids or liquids. Unlike aqueous liquids, which arerather easy to solidify due to their hydrogen bond forming ability, oilsare difficult to solidify.

Fatty Alcohol

In an embodiment, the second rheology modulator includes a fattyalcohol. The fatty alcohol which acts as an adjuvant is included in thegel and foamable compositions as a main constituent, to evolve thesolidifying effect of the gel and/or the foaming property of thecomposition and/or to stabilize the foam. In one or more embodiments,the fatty alcohol is selected from the group consisting of fattyalcohols having 15 or more carbons in their carbon chain, such as cetylalcohol and stearyl alcohol (or mixtures thereof). In one or moreembodiments, the fatty alcohol is selected from the group consisting offatty alcohols having 14 or more carbons in their carbon chain, such asmyristyl alcohol (with 14 carbons). Other examples of fatty alcohols arearachidyl alcohol (C20), behenyl alcohol (C22), tetracosanol,hexacosanol, octacosanol, triacontanol, tetratriacontanol,1-triacontanol (C30), as well as alcohols with longer carbon chains (upto C50). In one or more preferred embodiments, the fatty alcohol ismyristyl alcohol, cetyl alcohol, stearyl alcohol and combinationsthereof. Fatty alcohols, derived from beeswax and including a mixture ofalcohols, a majority of which has at least 20 carbon atoms in theircarbon chain, are suitable as fatty alcohols in the context herein. Incertain embodiments the amount of the fatty alcohol required to supportthe foam system can be approximately inversely related to the length ofits carbon chains. In one or more other embodiments, the fatty alcoholis selected from the group consisting of fatty alcohols having 14 orless carbons in their carbon chain, such as myristyl alcohol or laurylalcohol. In an embodiment the fatty alcohol is a solid at roomtemperature. Fatty alcohols are also useful in facilitating improvedspreadability and absorption of the composition.

Fatty alcohols are amphiphatic, however unlike customary surfactants,they do not usually function as stand-alone surfactants, because oftheir very weak emulsifying capacity. They are occasionally used asnon-ionic co-emulsifiers, i.e., and are commonly used as thickeners(Surfactants in personal care products and decorative cosmetics By LindaD. Rhein, Mitchell Schlossman, Anthony O'Lenick, P., Third Edition,2006, p. 247). Fatty alcohols are generally regarded as safe and theyare not considered as irritants.

An important property of the fatty alcohols used in context of thecomposition disclosed herein is related to their therapeutic propertiesper se. Long chain saturated and mono unsaturated fatty alcohols, e.g.,stearyl alcohol, erucyl alcohol, arachidyl alcohol and behenyl alcohol(docosanol) have been reported to possess antiviral, anti-infective,antiproliferative and anti-inflammatory properties. Longer chain fattyalcohols, e.g., tetracosanol, hexacosanol, heptacosanol, octacosanol,triacontanol, etc., are also known for their metabolism modifyingproperties and tissue energizing properties.

Fatty Acid

In an embodiment, the second rheology modulator further includes a fattyacid. The fatty acid which acts as an adjuvant is included in the geland foamable compositions to evolve solidifying effect of the gel and/orthe foaming property of the composition and/or to stabilize the foam. Inone or more embodiments the fatty acid can have 16 or more carbons inits carbon chain, such as hexadecanoic acid (C16), heptadecanoic acid,stearic acid (C18), arachidic acid (C20), behenic acid (C22),tetracosanoic acid (C24), hexacosanoic acid (C26, heptacosanoic acid(C27), octacosanoic acid (C28), triacontanoic acid, dotriacontanoicacid, tritriacontanoic acid, tetratriacontanoic acid andpentatriacontanoic acid as well as fatty acids with longer carbon chains(up to C50), or mixtures thereof. In one or more other embodiments, thefatty acid is selected from the group consisting of fatty acids having14 or less carbons in their carbon chain, such as dodecanoic acid,myristic acid, myristoleic acid, and lauric acid.

In certain embodiments, the carbon atom chain of the fatty acid may haveat least one double bond; alternatively, the fatty acid can be abranched fatty acid. The carbon chain of the fatty acid also can besubstituted with a hydroxyl group, such as 12-hydroxy stearic acid. Inan embodiment the fatty alcohol is a solid at room temperature. In oneor more preferred embodiments, the fatty acid is stearic acid.

Waxes

In certain embodiments the oleaginous second rheology modulator mayinclude a wax.

The wax which acts as an adjuvant in a gel and is included in the gel orfoamable compositions to evolve solidifying effect of the gel and/or thefoaming property of the composition and/or to stabilize the foam. Waxrefers to beeswax or another substance with similar properties. The termwax refers to a class of substances with properties similar to beeswax,in respect of (i) plastic behavior at normal ambient temperatures, amelting point above approximately 45° C., (iii) a relatively lowviscosity when melted (unlike many plastics); and (iv) hydrophobicnature. Suitable exemplary waxes which can be incorporated into theformulation include animal, vegetable, mineral or silicone based waxeswhich may be natural or synthetic such as, for example: beeswax, chinesewax, lanolin (wool wax), shellac wax, bayberry wax, candelilla wax,carnauba wax, castor wax, esparto wax, japan wax, ouricury wax, ricebran wax, soy wax, hydrogenated oil such ashydrogenated castor oil,hydrogenated cottonseed oil, or hydrogenated jojoba oil, mink wax, motanwax, ouricury wax, ozokerite, PEG-6 beeswax, rezowax, spent grain wax,stearyl dimethicone, paraffin waxes, such as paraffin 58-62° C.,paraffin 51-53° C. wax, paraffin 42-44° C. wax, and the like andmixtures thereof. In certain embodiments the term wax can extend tohydrogenated oils. In one or more embodiments the wax is selected from alist comprising of a solid wax, an animal wax, a vegetable wax, amineral wax, a natural wax or a synthetic wax. In certain embodimentsthe term wax can extend to hydrogenated oils. In an embodiment waxincludes polyolefins. In one or more preferred embodiments, the wax is abeeswax or hydrogenated castor oil.

In one or more embodiments, the wax is a polyolefin such aspolyethylene, polypropylene, polymethylpentene, polybutene, a polyolefinelastomer, polyisobutylene, ethylene propylene rubber, ethylenepropylene diene Monomer (M-class) rubber, polyethylene terephthalate,polydicyclopentadiene, linear polyolefins, branched polyolefins, cyclicpolyolefins, low density polyolefins, high density polyolefins,polyolefins with a low molecular weight, polyolefins with a highmolecular weight, halogenated polyolefins and the like and mixturethereof.

Combination of a Fatty Alcohol or a Fatty Acid and/or a Wax Togetherwith a Therapeutic Active Agent

Example 2 describes formulations where adding an active agent tooleaginous hydrophobic solvents does not affect viscosity of theformulation. When, however, the same formulation contains a fattyalcohol (or a mixture of fatty alcohols) or a fatty acid (or a mixtureof fatty acids) or a wax (or a mixture of waxes), or a combination of afatty alcohol with a wax or a fatty acid with a wax the therapeuticactive agent can, surprisingly, act synergistically to produce enhancedviscosity (Example 4). These successful combinations of an active agentand a fatty alcohol or a fatty acid or a wax or alternatively an activeagent and a fatty alcohol and/or a wax or a fatty acid and/or wax arereferred to herein as “viscosity inducing complexes”.

In one or more embodiments, the viscosity inducing complex is asynergistic combination of an active agent and a fatty alcohol (or amixture of fatty alcohols) or a fatty acid (or a mixture of fatty acids)or a wax or alternatively an active agent and a fatty alcohol (or amixture of fatty alcohols) and/or a wax (or a mixture of waxes) oralternatively an active agent and a fatty acid (or a mixture of fattyacids) and/or a wax (or a mixture of waxes).

In one or more embodiments, the viscosity inducing complex is asynergistic combination of a fatty alcohol (or a mixture of fattyalcohols) and a wax (or a mixture of waxes).

In one or more embodiments, the viscosity inducing complex is asynergistic combination of a fatty acid (or a mixture of fatty acids)and a wax (or a mixture of waxes).

In one or more embodiments the range of ratio of fatty alcohol to wax orfatty acid to wax can be about 100:1 to about 1:100; or about 90:1 toabout 1:45; or about 80:1 to about 1:40; or about 70:1 to about 1:35; orabout 60:1 to about 1:30; or about 50:1 to about 1:25; or about 40:1 toabout 1:20; or about 30:1 to about 1:15; or about 20:1 to about 1:10; orabout 15:1 to about 1:5; or about 10:1 to about 1:1; or any ranges inbetween such as 1:20 to 20:1, or preferably from 1:10 to 10:1.

In one or more embodiments the range of ratio of therapeutic solubleactive agent to second rheology modulator can be about 1:50000 to about250:1; or about 1:25000 to about 1:150; or about 1:10000 to about 100:1;or about 1:5000 to about 50:1; or about 1:2500 to about 1:25; or about1:1000 to about 10:1; or about 1:100 to about 1:1; or about 1:10 toabout 10:1 or any ranges in between.

Propellant

Certain compositions comprising a hydrophobic solvent, together with afirst rheology modulator (a suspended active agent) and a secondrheology modulator without any surface active agents result, uponpackaging in an aerosol container and adding a propellant, a shakableand homogenous foamable composition, which releases a breakable foamwith good to excellent quality (as defined herein).

Suitable propellants include volatile hydrocarbons such as butane,propane, isobutene or mixtures thereof. In one or more embodiments ahydrocarbon mixture AP-70 is used. In one or more other embodiments alower pressure hydrocarbon mixture AP-46 is used. Both contain butane,propane, isobutene although in different proportions. AP-70 is composedof about 50% w/w of propane, about 20% w/w of isobutane and about 30%w/w of propane. AP-46 is composed of about 16% w/w of propane, about 82%w/w of isobutane and about 2% w/w of propane Hydrofluorocarbon (HFC)propellants are also suitable as propellants in the context disclosedherein. Exemplary HFC propellants include 1,1,1,2 tetrafluoroethane(Dymel 134), and 1,1,1,2,3,3,3 heptafluoropropane (Dymel 227). Dimethylether is also useful. In one or more embodiments use of compressed gases(e.g., air, carbon dioxide, nitrous oxide, and nitrogen) is alsopossible.

In one or more embodiments a combination of at least two propellants,selected from HFC, hydrocarbon propellants, dimethyl ether andcompressed gases is contemplated.

Yet, in additional embodiments, the propellant is a self-foamingpropellant, i.e., a volatile liquid having a boiling point of less thanthe temperature of the target treatment site (such as the skin). Anexample of a post-foaming propellant is isopentane (bp=26° C.)

Any concentration of the propellant, which affords an acceptable foam isuseful in accordance with the present invention. In certain embodimentsthe propellant makes up between about 1% and about 30% of the foamablecomposition, or about 3% and 25%, preferably between about 5% and about16% of the composition. In other certain embodiments, the concentrationof the propellant is about 7% to about 17%; or about 10% to about 14% byweight of the total composition. The percent by weight is based onweight foamable composition. In preparing the formulations theingredients other than propellant are combined to 100% and thepropellant is added thereafter so that the ratio of formulation otherthan propellant to propellant can range from 100:1 to 100:30 or fromabout 100:3 to about 100:25; or from about 100:4 to about 100:24; orfrom about 100:7 to about 100:17; or from about 100:10 to about 100:14or preferably 100:5 to 100:16. Yet, in additional embodiments, the ratioof composition other than propellant to propellant is between about100:20 and about 100:50.

In one or more embodiments the propellant can also be used to expelformulation using a bag in can system or a can in can system as will beappreciated by someone skilled in the art. In certain embodiments thepart of the propellant system is in the formulation and part separatefrom the formulation. In this way it is possible to reduce the amount ofsurfactant in the formulation but still provide good expulsion from thecanister, where the foamable formulation is expelled quickly but withoutjetting or noise.

In one or more embodiments a foam formulation is expelled from astandard pressurized canister where the propellant is part offormulation. Formulations can be expelled or helped to be expelled byusing propellant which is separate from the formulation using a bag incan or can in can system. Although, these systems can be used withcompressed air the pressure may not be sufficient to expel theformulation through the device and higher pressure propellant such asAP70 should be selected. In one or more embodiments, the formulation ispackaged in bag in can systems or in can in can system. In one or moreembodiments, the formulation is expelled from the canister using thepressure provided by the propellant mixed with the formulation. In oneor more embodiments, the formulation is expelled from the canister usingthe pressure provided by the propellant stored in a compartmentsurrounding the formulation. According to other embodiments part of thepropellant system is in the formulation and part of the propellantsystem is separate from the formulation, which is used to expel saidformulation using a bag or can in can system. In this way it is possibleto reduce the amount of propellant within the formulation and avoidunwanted gaseous effects, for example in vaginal applications, but stillprovide good expulsion from the canister, where the foamable formulationis expelled sufficiently quickly but without jetting or noise. So by wayof example, between about 1% to 3%; or between about 2% to 4%; betweenabout 3% to 5% propellant (ratio of formulation to propellant of 100:1to 3; 100:2 to 4; 100:3 to 5; respectively) is part of the formulationand a further amount of propellant is separate form the formulation andhelps expel the formulation. In one or more embodiments a similar amountof propellant is in the formulation and a pump or other mechanical meansis used to provide the additional expulsion force.

In one or more embodiments there is provided a composition comprising apropellant having a vapor pressure between about 10 psi and about 130psi. In one or more embodiments there is provided a compositioncomprising a propellant which is hydrocarbon propellant or ahydrofluorocarbon or another environmentally acceptable propellant.

In an embodiment foam quality may be improved by increasing thepropellant, by say aliqots of 2% or 4%, for example, from 8% to about12%. The actual amount of propellant increase that is suitable should betitrated from formulation to formulation.

Stability Modulating Agent

In one or more embodiments a stability modulating agent is used in awaterless or substantially waterless composition. The term stabilitymodulating agent is used to describe an agent which can improve thestability of, or stabilize a carrier or a foamable composition and/or anactive agent by modulating the effect of a substance or residue presentin the carrier or composition. The substance or residue may, forexample, be acidic or basic or buffer system (or combinations thereof)and potentially alter an artificial pH in a waterless or substantiallynon-aqueous environment, such as, by acting to modulate the ionic orpolar characteristics and any pH balance of a waterless or substantiallynon-aqueous carrier, composition, gel, foamable carrier or foamablecomposition or resultant foam or it may be a chelating or sequesteringor complexing agent or it may be one or more metal ions which may act asa potential catalyst in a waterless or substantially non-aqueousenvironment or it may be an ionization agent or it may be an oxidizingagent.

Dermatologic Excipients

In one or more embodiments the formulation may comprise excipients thatare suitable for dermatologic use. In one or more embodiments, thehydrophobic carrier composition further contains an anti-infectiveagent, selected from the group of an antibiotic agent, an antibacterialagent, an antifungal agent, an agent that controls yeast, an antiviralagent and an antiparasitic agent. In a preferred embodiment the antiinfective agent comprises a tetracycline antibiotic. As has beenpreviously shown in U.S. Provisional Application No. 61/248,144 filedOct. 2, 2009 and titled “Surfactant-Free Water-Free FoamableCompositions, Breakable Foams And Their Uses,” and in U.S. ProvisionalApplication No. 61/322,148 filed Apr. 8, 2010 and titled“Surfactant-Free Water-Free Foamable Compositions, Breakable Foams AndGels And Their Uses,” which are incorporated herein in their entirety byreference, combining the anti-infective effect of a hydrophobic carriercomposition, with an anti-infective agent can result in a synergisticeffect increasing the anti-infective effect and consequently highersuccess rate of the treatment is attained. According to the presentapplication it has surprisingly been shown that combination of an activeagent with second rheology modulator achieves a viscous formulation inwhich the active pharmaceutical ingredient is chemically stable and theformulation is physically stable as demonstrated herein in the Examples.Moreover the use of hydrophobic based water free formulation has beenpreviously shown in said provisional application to maximize theantimicrobial potential of the formulations. Storage in sealed, lightand airtight canisters can assist in preserving the formulations.

Ophthalmic Excipients

In one or more embodiments the formulation may comprise excipients thatare suitable for ophthalmic use. By virtue of their suitability forophthalmic use they may in certain embodiments be applicable on othersensitive targets such as for use internal and/or external wounds orburns or in body cavities. Excipients selected as part of a drug carrierthat can be used with the active pharmaceutical ingredients areidentified by compatibility studies with active ingredients to ascertainwhich are compatible for use with the active pharmaceutical agents, forexample, by examining which do not react with and/or promote break downof the active pharmaceutical ingredients. [0147] Oleaginous ointmentsare viscous preparations, which remain viscous when applied to the skinor other body surfaces; and they require extensive rubbing. Because oftheir viscosity, eye ointments cause blurred vision and consequent lowtolerability, especially for long term treatment. Because of their highviscosity, drugs are trapped in the vehicle and cannot migrate throughto their target site of action, for example, the skin or the eye.

Liquid, non viscous oleaginous medications are also disadvantageous, asthey spill easily and thus, are very inconvenient to use. In eyetreatment, liquid drops are difficult to apply and they require lying onthe back at rest for accurate administration. Furthermore, because oftheir low viscosity, liquid oil vehicles cannot carry suspended drugs,which tend to precipitate and if the viscosity is not high enough,thereby impairing the uniformity of the therapeutic product.

In one or more embodiments the formulations are not highly viscous; andthey may be flowable. In one or more embodiments the formulations arethixotropic so that on application of shear force their viscositydecreases and they become more flowable. In one or more embodiments theformulations are foams which are breakable on shear force. In one ormore embodiments the foams are based on gel formulations, which arethixotropic so that on application of shear force their viscositydecreases and they become more flowable. In one or more embodiments theviscosity of the formulation prior to addition of propellant is morethan about 1000 cPs and less than about 25,000 cPs.

Additional Components

In an embodiment, a composition disclosed herein includes one or moreadditional components. Such additional components include but are notlimited to anti perspirants, anti-static agents, bulking agents,cleansers, colorants, skin conditioners, deodorants, diluents, dyes,fragrances, hair conditioners, herbal extracts, humectants, keratolyticagents, modulating agents, pearlescent aids, perfuming agents, pHmodifying or stabilizing agents, skin penetration or permeationenhancers, softeners, solubilizers, sunscreens, sun blocking agents,sunless tanning agents, viscosity modifiers, flavanoids and vitamins. Asis known to one skilled in the art, in some instances a specificadditional component may have more than one activity, function oreffect.

In certain embodiments, the additional component is an oil solublepreservative, or an oil soluble antioxidant, or an oil soluble radicalscavenger, or an oil soluble complexing agent, or an oil soluble pigmentor dye.

Definitions

All % values are provided on a weight (w/w) basis.

By the term “about” herein it is meant as indicated above and that afigure or range of figures can vary in an embodiments plus or minus upto 30%. So in this embodiment if a figure of “about 1” is provided thenthe amount can be up to 1.3 or from 0.70. In other embodiments it canreflect a variation of plus or minus 20%. In still further embodimentsit can describe a variation of plus or minus 10%. In still furtherembodiments it can describe a variation of plus or minus 5%. As will beappreciated by one of the art there is some reasonable flexibility informulating compositions such that where one or more ingredients arevaried successful formulations may still be made even if an amount fallsslightly outside the range. Therefore, to allow for this possibilityamounts are qualified by about. In one or more other embodiments thefigures may be read without the prefix about.

The term “thixotropic,” as used herein, means that the formulation showsa significant decrease in viscosity upon application of shear force.

The term “waterless,” as used herein, means that the compositioncontains no, or substantially no, free or unassociated or absorbedwater. Similarly, “waterless” or “substantially waterless” carrierscontain at most incidental and trace amounts of water.

By the term “single phase” herein it is meant that the liquid componentsof the composition or carrier are fully miscible, and the solidcomponents if any, are either dissolved or suspended in the composition.By substantially a single phase is meant that the composition or carrieris primarily or essentially a single phase as explained above, but mayalso have present a small amount of material which is capable of formingor may form a separate phase amounting to less than about 5% of thecomposition or carrier, preferably less than about 3%, and morepreferably less than about 1%. By the term “single phase” or“substantially a single phase” in the context of a foamable compositionthe above meaning applies even after addition of propellant to thecomposition or carrier.

The term “unstable active agent” as used herein, means an active agentwhich is oxidized and/or degraded within less than a day, and in somecases, in less than an hour upon exposure to air, light, skin or waterunder ambient conditions.

The term “co-surfactant” as used herein, means a molecule which on itsown is not able to form and stabilize satisfactorily an oil in wateremulsion but when used in combination with a surfactant theco-surfactant has properties, which can allow it to help surfactants tocreate an emulsion and can boost the stabilizing power or effect of thesurfactant and can include, for example, a fatty alcohol, such as cetylalcohol or a fatty acid such as stearic acid. Cetyl alcohol is a waxyhydrophobic substance that can be emulsified with water using asurfactant. Some substances may have more than one function and forexample, fatty alcohols can in some formulations act as a co-solvent. Incertain circumstances a co-surfactant can itself be converted in to asurfactant or soap by, for example, adding a base, such as,triethanolamine to a fatty acid like stearic acid.

The identification of a “polyol”, as used herein, is an organicsubstance that contains at least two hydroxy groups in its molecularstructure.

In one or more embodiments, the polyol is a diol (a compound thatcontains two hydroxy groups in its molecular structure). Examples ofdiols include propylene glycol (e.g., 1,2-propylene glycol and1,3-propylene glycol), butanediol (e.g., 1,2-butanediol, 1,3-butanediol,2,3-butanediol and 1,4-butanediol), butanediol (e.g., 1,3-butanediol and1,4-butenediol), butynediol, pentanediol (e.g., pentane-1,2-diol,pentane-1,3-diol, pentane-1,4-diol, pentane-1,5-diol, pentane-2,3-dioland pentane-2,4-diol), hexanediol (e.g., hexane-1,6-diol hexane-2,3-dioland hexane-2,56-diol), octanediol (e.g., 1,8-octanediol), neopentylglycol, 2-methyl-1,3-propanediol, diethylene glycol, triethylene glycol,tetraethylene glycol, dipropylene glycol and dibutylene glycol.

In one or more embodiments, the polyol is a triol (a compound thatcontains three hydroxy groups in its molecular structure), such asglycerin, butane-1,2,3-triol, butane-1,2,4-triol and hexane-1,2,6-triol.

In one or more embodiments, the polyol is a saccharide. Exemplarysaccharides include, but are not limited to monosaccharide,disaccharides, oligosaccharides and sugar alcohols.

A monosaccharide is a simple sugar that cannot be hydrolysed to smallerunits. Empirical formula is (CH2O)n and range in size from trioses (n=3)to heptoses (n=7). Exemplary monosaccharide compounds are ribose,glucose, fructose and galactose.

Disaccharides are made up of two monosaccharides joined together, suchas sucrose, maltose and lactose.

In one or more embodiments, the polyol is a sugar alcohol (also known asa polyol, polyhydric alcohol, or polyalcohol) is a hydrogenated form ofsaccharide, whose carbonyl group (aldehyde or ketone, reducing sugar)has been reduced to a primary or secondary hydroxyl group. They arecommonly used for replacing sucrose in foodstuffs, often in combinationwith high intensity artificial sweeteners to counter the low sweetness.Some exemplary sugar alcohols, which are suitable for use according tothe present application are mannitol, sorbitol, xylitol, maltitol,lactitol. (Maltitol and lactitol are not completely hydrogenatedcompounds—they are a monosaccharide combined with a polyhydric alcohol.)Mixtures of polyols, including (1) at least one polyol selected from adiol and a triol; and (2) a saccharide are contemplated within the scopeof the present disclosure.

According to some embodiments, the composition is polyol free i.e., freeof polyols. In other embodiments, the composition is substantially freeand comprises less than about 5% final concentration of polyols,preferably less than 2%, more preferably less than 1%. Where aformulation includes insignificant amounts of polyols it is consideredto be essentially free of them.

In an embodiment, the polyol is linked to a hydrophobic moiety. In thecontext of the present disclosure, a polyol linked to a hydrophobicmoiety is still defined as a “polyol” as long as it still contains twoor more free hydroxyl groups.

In an embodiment, the polyol is linked to a hydrophilic moiety. In thecontext of the present disclosure, a polyol linked to a hydrophilicmoiety is still defined “polyol” as long as it still contains two ormore free hydroxyl groups.

The term “water activity” as used herein, activity represents thehydroscopic nature of a substance; or the tendency of a substance thatabsorbs water from its surroundings. Microorganisms require water togrow and reproduce, and such water requirements are best defined interms of water activity of the substrate. The water activity of asolution is expressed as Aw=P/Po, where P is the water vapor pressure ofthe solution and Po is the vapor pressure of pure water at the sametemperature. Every microorganism has a limiting Aw, below which it willnot grow; e.g., for Streptococci, Klebsiella spp, Escherichia coli,Clostridium perfringens, and Pseudomonas spp, the Aw value is 0.95.Staphylococcus aureus is most resistant and can proliferate with an Awas low as 0.86, and fungi can survive at Aw of at least 0.7. In one ormore embodiments, the concentration of the hydrophobic solvent, and/orsecond rheology modulator in the composition is selected to provide anAw value selected from the ranges of (1) about 0.8 and about 0.9; (2)about 0.7 and about 0.8; and (3) less than about 0.7. By delivering theformulation in a pressurized package does not allow for humidity to beabsorbed by the preparation, and therefore, the water free character ofthe composition cannot be damaged.

In an embodiment no preservative is added because the formulation is awaterless hydrophobic solvent or oil-based formulation having an Aw(Water Activity) value of less than 0.9, less, or less than about 0.8,or less than about 0.7 or less than about 0.6 and preferably less thanabout 0.5 which is below the level of microbial proliferation.

The identification of a “solvent,” as used herein, is not intended tocharacterize the solubilization capabilities of the solvent for anyspecific active agent or any other component of the composition. Rather,such information is provided to aid in the identification of materialssuitable for use as a part in the carriers described herein.

Substantially Alcohol Free

Lower or short chain alcohols, having up to 5 carbon atoms in theircarbon chain skeleton, such as ethanol, propanol, isopropanol, butanol,iso-butanol, t-butanol and pentanol are considered less desirablesolvents or co-solvents due to their skin-irritating effect. Thus,according to some embodiments, the composition is substantiallyalcohol-free i.e., free of short chain alcohols. In other embodiments,the composition comprises less than about 5% final concentration oflower alcohols, preferably less than 2%, more preferably less than 1%.Where a formulation contains insignificant amounts of short chainalcohols it is considered to be essentially free of them.

Substantially Standard Surfactant Free

Surfactants have been categorized in to various sub classes depending onthere ionic characteristics, namely non-ionic surfactants, anionic,cationic, zwitterionic, amphoteric and amphiphilic surfactants. The termsurfactant has been often loosely used in the art to include substanceswhich do not function effectively as stand alone surfactants to reducesurface tension between two substances or phases. Reduction of surfacetension can be significant in foam technology in relation to the abilityto create small stable bubbles. For example fatty alcohols, fatty acidsand certain waxes are amphiphatic, are essentially hydrophobic with aminor hydrophilic region and for the purposes of forming an emulsionunlike standard or customary surfactants, are not effective asstand-alone surfactants in foamable emulsion compositions, because oftheir very weak emulsifying capacity on their own. They are occasionallyused in a supporting role as co-emulsifiers, i.e., in combination with astandard surfactant but are commonly used as thickeners and havesuccessfully been used as foam adjuvants to assist customary surfactantsto boost foam quality and stability. For clarification in the contextherein whilst the term “standard surfactant” or “customary surfactant”refers herein to customary non-ionic, anionic, cationic, zwitterionic,amphoteric and amphiphilic surfactants a fatty alcohol or a fatty acidand certain waxes are not regarded as a standard surfactant. However, incontrast, an ether or an ester formed from such fatty alcohols or fattyacids can be regarded as a customary surfactant. Many standardsurfactants are, derivatives of fatty alcohols or fatty acids, such asan ethers or an esters formed from such fatty alcohols or fatty acidswith hydrophilic moieties, such as polyethyleneglycol (PEG) can beregarded as a customary surfactant. However, a native, (non derivatized)fatty alcohols or a fatty acids, or as well as waxes are not regarded asa standard surfactant.

Generally, surfactants are known to possess irritation potential. Oneway that is used to try and reduce potential irritation and drying ofthe skin or mucosa due to surfactants and their repeated use especiallywhen formulations are to be left on the skin or mucosa rather than beingwashed off is to use essentially or primarily non ionic surfactants atpreferably low concentrations below 5%. The current breakthrough ofidentifying formulations which produce quality breakable foam yetomitting customary surfactants from a composition may contribute toimproved tolerability of such a composition and can be an importantadvantage. This is especially so when a formulation is to be applied toa very sensitive target site, and particularly so on a repeated basis.

Non-limiting examples of classes of customary non-ionic surfactantsinclude: (i) polyoxyethylene sorbitan esters (polysorbates), such aspolysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80; (ii)sorbitan esters, such as sorbitan monostearate sorbitan monolaurate andsorbitan monooleate; (iii) polyoxyethylene fatty acid esters, such asPEG-8 stearate, PEG-20 stearate, PEG-40 stearate, PEG-100 stearate,PEG-8 laurate, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-8oleate, PEG-9 oleate, PEG-10 oleate, PEG-12 oleate, PEG-15 oleate andPEG-20 oleate; (iv) PEG-fatty acid diesters, such as PEG-150 distearate;(v) polyethylene glycol (PEG) ethers of fatty alcohols; (vi) glycerolesters, such as glyceryl monostearate, glyceryl monolaurate, glycerylmonopalmitate and glyceryl monooleate; (vii) PEG-fatty acid mono- anddi-ester mixtures; (viii) polyethylene glycol glycerol fatty acidesters; (ix) propylene glycol fatty acid esters; (x) mono- anddiglycerides; (xi) sugar esters (mono-, di- and tri-esters of sucrosewith fatty acids) and (xii) polyethylene glycol alkyl phenols.

In certain embodiments, the composition is free of customarysurfactants, or “surfactant-free” and in certain embodiments thefoamable composition is substantially free of customary surfactants, or“substantially surfactant-free”. In certain alternative embodiments, thecomposition comprises a surfactant.

In the context herein, the term “substantially surfactant-freecomposition” relates to a composition that contains a total of less thanabout 0.4% of a surfactant selected from the group consisting ofcustomary non-ionic, anionic, cationic, zwitterionic, amphoteric andampholytic surfactants. Preferably, the composition comprises less thanabout 0.2% by weight of a standard surfactant and more preferably lessthan about 0.1%. Where a formulation includes insignificant amounts ofsurfactants it is considered to be essentially free of them.Non-surfactant or surfactant-free compositions will comprise no ornegligible levels of surface active agents.

In additional embodiments, the term “substantially surfactant-free”relates to a composition wherein the ratio between the foamer complexand the surfactant is between 10:1 or 5:1; or between 20:1 and 10:1 orbetween 100:1 and 20:1.

In certain embodiments, the composition is free or substantially free ofan ionic surfactant. In certain embodiments, the composition is free orsubstantially free of a non-ionic surfactant.

Substantially Polymer Free

By the term polymeric agent it is intended to mean a compound havingmultiple repeated units such as cellulose polymers, acrylic polymers,block polymers and copolymers. In one or more certain embodiments thepolymeric agent has a molecular weight of in excess of a 1000 Daltons.Unexpectedly, it has been discovered that quality oleaginousformulations and foams can be achieved without the presence ofsignificant amounts of standard polymeric agents known in the art (e.g.gelling agents). Thus, in one or more embodiments, there is provided asubstantially surfactant free and substantially polymeric agent freeoleaginous formulation or foam. In one or more preferred embodiments theoleaginous formulations and foams are free of surface active agents andpolymers. Unexpectedly, it has further been discovered that qualityoleaginous formulations and foams can be achieved without the presenceof significant amounts of standard surfactants, foam adjuvants andpolymeric agents known in the art. Thus, in one or more embodiments,there is provided a substantially surfactant free and substantiallypolymeric agent free oleaginous formulation or foam. In one or morepreferred embodiments the oleaginous formulations and foams are free ofsurface active agents and polymeric agents.

By the term polymeric agent it is intended to mean a compound havingmultiple repeated units such as cellulose polymers, acrylic polymers,block polymers and copolymers. In one or more embodiments the number ofmultiple or repeating units is at least 4. In one or more embodimentsthe oleaginous formulations are substantially polymer free. In one ormore embodiments the oleaginous formulations are substantially polymerfree of a polymeric agent selected from the group consisting of abioadhesive agent, a gelling agent, a film forming agent and a phasechange agent, being locust bean gum, sodium alginate, sodium caseinate,egg albumin, gelatin agar, carrageenin gum, sodium alginate, xanthangum, quince seed extract, tragacanth gum, guar gum, cationic guars,hydroxypropyl guar gum, starch, amine-bearing polymers such as chitosan;acidic polymers obtainable from natural sources, such as alginic acidand hyaluronic acid; chemically modified starches and the like,carboxyvinyl polymers, polyvinylpyrrolidone, polyvinyl alcohol,polyacrylic acid polymers, polymethacrylic acid polymers, polyvinylacetate polymers, polyvinyl chloride polymers, polyvinylidene chloridepolymers, semi-synthetic polymeric materials such as cellulose ethers,such as methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl cellulose, hydroxy propylmethyl cellulose,methylhydroxyethylcellulose, methylhydroxypropylcellulose,hydroxyethylcarboxymethylcellulose, carboxymethyl cellulose,carboxymethylcellulose carboxymethylhydroxyethylcellulose, and cationiccelluloses, carbomer (homopolymer of acrylic acid is crosslinked with anallyl ether pentaerythritol, an allyl ether of sucrose, or an allylether of propylene); poloxamers (synthetic block copolymer of ethyleneoxide and propylene); polyethylene glycol having molecular weight of1000 or more (e.g., PEG 1,000, PEG 4,000, PEG 6,000 and PEG 10,000) andwhich could function as a hydro alcoholic foam booster. By substantiallypolymer free it is intended to mean less than about 5%, preferably lessthan about 2%. By essentially polymer free it is intended to mean lessthan about 1%, preferably less than about 0.5%. In further embodimentsthey are essentially polymer free and in still further embodiments theyare free of polymeric agents. In alternative embodiments the oleaginousformulations may comprise a polymeric agent in such case the polymericagents are oil soluble polymeric agents. Non limiting examples ofoil-soluble polymeric agents are: Ethyl cellulose, alkylated guar gum,trimethylsiloxysilicate, alkyl-modified silicone, polyamide-modifiedsilicone, homopolymers and copolymers of alkyl methacrylates, alkylacrylates, and alkyl styrenes, polyisobutene, polybutyl metacrylate,polycyclohexylstyrene.

According to one or more embodiments, the composition comprises lessthan about 0.1% by weight of a polymeric agent and more preferably lessthan about 0.05%. Polymer free compositions will comprise no ornegligible levels of polymeric agents.

In the art, the term polymeric agent can be used loosely to refer to anypolymer. However, in some embodiments polymers that do not have a gelbuilding role but may act in other ways are not excluded from thecompositions. In one or more embodiments a polyether siloxane copolymerand a poly(dimethylsiloxane)-(diphenyl-siloxane) copolymer and the like,which can provide a good feeling to the composition are not excluded.

Physical Characteristics of the Gels and Foamable Composition and Foam

A composition manufactured according to one or more embodiments hereinis very easy to use. When applied onto the afflicted body surface ofmammals, i.e., humans or animals, it is in a gel or foam state, allowingfree application without spillage. Upon further application of amechanical force, e.g., by rubbing the composition onto the bodysurface, it freely spreads on the surface and is rapidly absorbed.

In one or more embodiments the composition is a single phase solution.In one or more embodiments the composition is substantially a singlephase solution. In certain circumstances, where the active agent isinsoluble and is presented as a homogenous suspension, the formulationis turbid or cloudy.

In one or more embodiments the composition has an acceptable shelf-lifeof at least one year, or at least two years at ambient temperature. Afeature of a product for cosmetic or medical use is long term stability.Propellants, which are a mixture of low molecular weight hydrocarbons,tend to impair the stability. The foamable compositions herein aresurprisingly stable, even in the absence of customary surfactants.Following accelerated stability studies, they demonstrate desirabletexture; they form fine bubble structures that do not break immediatelyupon contact with a surface, spread easily on the treated area andabsorb quickly.

In certain embodiments the composition should also be free flowing, toallow it to flow through the aperture of the container, e.g., gel tubeor an aerosol container, and provide an acceptable gel or foam.Compositions containing a substantial amount of semi-solid hydrophobicsolvents, e.g., white petrolatum, as the main ingredients of the oilphase of the emulsion, will likely exhibit high viscosity and poorflowability and can be inappropriate candidates for a foamablecomposition. Thus in one or more embodiments semi-solid hydrophobicsolvents are a subsidiary component in the composition, for examplebeing present at less than about 25%, less than about 20%, less thanabout 15%, less than about 10%, or less than about 5% by weight of thefoamable composition. In other embodiments they can be present in higheramounts due to the solvent effect e.g of a liquid solvent or of thepropellant diluting the formulation and enabling flowability or wherethe formulation is presented as a gel or ointment.

Foam Quality

Foam quality can be graded as follows:

Grade E (excellent): very rich and creamy in appearance, does not showany bubble structure or shows a very fine (small) bubble structure; doesnot rapidly become dull; upon spreading on the skin, the foam retainsthe creaminess property and does not appear watery.

Grade G (good): rich and creamy in appearance, very small bubble size,“dulls” more rapidly than an excellent foam, retains creaminess uponspreading on the skin, and does not become watery.

Grade FG (fairly good): a moderate amount of creaminess noticeable,bubble structure is noticeable; upon spreading on the skin the productdulls rapidly and becomes somewhat lower in apparent viscosity.

Grade F (fair): very little creaminess noticeable, larger bubblestructure than a “fairly good” foam, upon spreading on the skin itbecomes thin in appearance and watery.

Grade P (poor): no creaminess noticeable, large bubble structure, andwhen spread on the skin it becomes very thin and watery in appearance.

Grade VP (very poor): dry foam, large very dull bubbles, difficult tospread on the skin.

Topically administrable foams are typically of quality grade E or G,when released from the aerosol container. Smaller bubbles are indicativeof a more stable foam, which does not collapse spontaneously immediatelyupon discharge from the container. The finer foam structure looks andfeels smoother, thus increasing its usability and appeal.

Foam Density

Another property of the foam is specific gravity or density, as measuredupon release from the aerosol can. Typically, foams have specificgravity of less than 0.50 g/mL or less than 0.12 g/mL, depending ontheir composition and on the propellant concentration. In one or moreembodiments the foam density is about less than 0.3 g/mL.

Shakability

‘Shakability’ means that the composition contains some or sufficientflow to allow the composition to be mixed or remixed on shaking. Thatis, it has fluid or semi fluid properties. Shakability is describedfurther in the section on Tests. In one or more certain limitedembodiments the formulation is poorly shakable but is neverthelessflowable.

Breakability/Collapse Time

A further optional aspect of the gel or foam is breakability. Thebalance between stability and breakability of the gel or foam coming outof the container is very delicate: on one hand the gel or foam may notbe “quick breaking”, i.e., it should be stable upon release from thepressurized container and not break as a result of exposure to skintemperature; and on the other hand, it should be “breakable”, i.e., itshould spread easily, break down and absorb into the skin or membraneupon application of mild shear force. The breakable gel or foam isthermally stable, yet breaks under shear force. Shear-force breakabilityof the gel or foam is clearly advantageous over thermally-inducedbreakability. Thermally sensitive gels or foams start to collapseimmediately upon exposure to skin temperature and, therefore, cannot beapplied on the hand and afterwards delivered to the afflicted area.

The collapse time of a gel or foam represents its tendency to betemperature-sensitive and its ability to be at least stable in the shortterm so as to allow a user sufficient time to comfortably handle andapply the gel or foam to a target area without being rushed and/orconcerned that it may rapidly collapse, liquefy and/or disappear.Collapse time, as an indicator of thermal sensitivity, is examined bydispensing a given quantity of gel or foam and photographingsequentially its appearance with time during incubation at 36° C. Simplecollapse time can be measured by applying a gel or foam sample on a bodysurface like the fingers at normal body temperature of about 37° C.

Oils may cause foam to be thermolabile and “quick breaking.” However, incertain embodiments herein, despite the presence of high oil content,quite unexpectedly the foam is substantially thermally stable. By“substantially thermally stable” it is meant that the foam uponapplication onto a warm skin or body surface at about 35-37° C. does notcollapse within about 30 seconds. Thus, in one or more embodiments thesimple collapse time of the foam is more than about 30 seconds or morethan about one minute or more than about two minutes. In one or morelimited embodiments simple collapse time can be a little shorter than 30seconds, but not less than about 20 seconds. In one or further oralternative embodiments the collapse time is measured by introducing asample of foam into an incubator at 36° C. and the collapse time of thefoam is more than 30 seconds or more than about one minute or more thanabout two minutes.

There are many applications for a gel or foam of the present invention.Below is a non-limiting list of applications which are provided todemonstrate the versatility of such a composition and method formodulating an oleaginous formulation viscosity. While many of suchapplications are in the healthcare and cosmetic area, adding a rheologymodulator to waxes in oleaginous compositions can be extended toapplications outside the pharmaceutical and cosmetic fields, includingfor example mechanics, electronics, food industry, safety, sanitationetc.

Pharmaceutical Composition

The oleaginous composition of the present invention can be used byitself as a topical treatment of a body surface, as many hydrophobicsolvents such as emollients, unsaturated oils, essential oils ortherapeutic oils that possess cosmetic or medical beneficial effects.Furthermore, it is an ideal vehicle for active pharmaceuticalingredients and active cosmetic ingredients. In the context activepharmaceutical ingredients and active cosmetic ingredients arecollectively termed “active agent” or “active agents”. The absence ofsurfactants in the composition is especially advantageous, since nosurfactant-related adverse reactions are expected from such acomposition. Some surfactants may act to facilitate gelling of thepre-foam formulation. In one or more embodiments the active agent issoluble in the composition of a phase thereof. In one or more otherembodiments it is partially soluble or insoluble. When partially solubleor insoluble the active agent is presented as a suspension or it can beencapsulated in a carrier. In one or more embodiments the active agentis a rheology modifying active agent. In one or more embodiments theactive agent is a non rheology modifying active agent. In one or moreembodiments a rheology modifying active agent and a non rheologymodifying active agent can be used in combination.

Suitable active agents include but are not limited to an active herbalextract, an acaricides, an age spot and keratose removing agent, anallergen, an alpha hydroxyl acid, an analgesic agent, an androgen, anantiacne agent, an antiallergic agent, an antiaging agent, anantibacterial agent, an antibiotic, an antiburn agent, an anticanceragent, an antidandruff agent, an antidepressant, an antidermatitisagent, an antiedemic anent, an antifungal agent, an antihistamine, anantihelminth agent, an anti-hyperkeratosis agent, an anti-infectiveagent, an antiinflammatory agent, an antiirritant, an antilipemic agent,an antimicrobial agent, an antimycotic agent, an antioxidant, anantiparasitic agent, an antiproliferative agent, an antipruritic agent,an antipsoriatic agent, an antirosacea agent, an antiseborrheic agent,an antiseptic agent, an antiswelling agent, an antiviral agent, ananti-wart agent, an anti-wrinkle agent, an anti-yeast agent, anastringent, a beta-hydroxy acid, benzoyl peroxide, a cardiovascularagent, a chemotherapeutic agent, a corticosteroid, an immunogenicsubstance, a dicarboxylic acid, a disinfectant, an estrogen, afungicide, a hair growth regulator, a haptene, a hormone, a hydroxyacid, an immunosuppressant, an immunoregulating agent, animmunomodulator, an immunostimulant, an insecticide, an insectrepellent, a keratolytic agent, a lactam, a local anesthetic agent, alubricating agent, a masking agent, a metal, a metal oxide, a mitocide,a neuropeptide, a non-steroidal anti-inflammatory agent, an oxidizingagent, a pediculicide, a peptide, a pesticide, a progesterone, aprotein, a photodynamic therapy agent, a radical scavenger, a refattingagent, a retinoid, a sedative agent, a scabicide, a self tanning agent,a skin protective agent, a skin whitening agent, a steroid, a steroidhormone, a vasoactive agent, a vasoconstrictor, a vasodilator, avitamin, a vitamin A, a vitamin A derivative, a vitamin B, a vitamin Bderivative, a vitamin C, a vitamin C derivative, a vitamin D, a vitaminD derivative, a vitamin D analog, a vitamin F, a vitamin F derivative, avitamin K, a vitamin K derivative, a wound healing agent and a wartremover. According to a further embodiment the active agent is atetracycline antibiotic. In certain embodiments the tetracycline isminocycline. In certain embodiments the tetracycline is doxycycline. Incertain embodiments the agent is selected from a group consisting ofcalcitriol, mometasone fuorate, calcitriol and lidocaine. As is known toone skilled in the art, in some instances a specific active agent mayhave more than one activity, function or effect. According to a furtherembodiment the active agent is chemically stable for at least two monthsand where the active agent is compatible with the other ingredients.According to a further embodiment the active agent is chemically stablefor at least six months; or for at least nine months for at least twelvemonths; or for at least fifteen months; or for at least eighteen months;or for at least twenty one months; or for at least twenty four months.

Encapsulation of an Active Agent

In one or more embodiments, the active agent is encapsulated inparticles, microparticles, nanoparticles, microcapsules, microspheres,nanocapsules, nanospheres, liposomes, niosomes, polymer matrix,silica-gel, graphite, nanocrystals or microsponges. Such particles canhave various functions, such as (1) protection of the drug fromdegradation; (2) modification of the drug release rate from thecomposition; (3) control of skin penetration profile; and (4) mitigationof adverse effects, due to the controlled release of the active agentfrom the encapsulation particles.

Solubility of an Active Agent

Solubility of the steroid is an important factor in the development of astable composition according to the present invention.

For definition purposes, in the context of the present invention, thedescriptive terminology for solubility according to the US Pharmacopoeia(USP 23, 1995, p. 10), the European Pharmacopoeia (EP, 5^(th) Edition(2004), page 7) and several other textbooks used in the art ofpharmaceutical sciences (see for example, Martindale, The ExtraPharmacopoeia, 30^(th) Edition (1993), page xiv of the Preface; andRemington's Pharmaceutical Sciences, 18^(th) Edition (1990), page 208)is adapted:

Parts of Descriptive Term Solvent Required for 1 Part of Solute Verysoluble Less than 1 Freely soluble From 1 to 10 Soluble From 10 to 30Sparingly soluble From 30 to 100 Slightly soluble From 100 to 1,000 Veryslightly soluble From 1,000 to 10,000 Practically insoluble or Insoluble10,000 and over

In preferred embodiments of the present invention, the active agent,which constitutes the first rheology modulator is not soluble or ispartially soluble and all or part thereof, is suspended in thecomposition. Thus, in one or more embodiments, the active agent ispresent in the composition in a concentration which is higher thanprescribed in the above table for such an active agent.

Yet, in one or more embodiments, the active agent is insoluble i.e.,“requires 10,000 parts or more of a solvent to be solubilized”, in thecomposition.

In certain embodiments it is desirable that the active agent ismaximally soluble in the composition, because solubility of the activeagents is expected to increase its bioavailability.

Yet, in additional embodiments it is desirable that the active agent isinsoluble in the composition, because its degradation is enhanced whenit is dissolved. In such cases, the hydrophobic solvent is selected by(1) testing the solubility of said active agent in various hydrophobicsolvents, followed by (2) inclusion in the composition of such solventsthat do not solubilize the active agent. In one or more embodiments theactive agent is presented as a suspension. In one or more furtherembodiments the active agent is micronized, which can assist in deliveryinto the skin, mucosal membrane and body cavity surfaces and also aidhomogenous distribution within the formulation. In effect, part of theactive agent is presented to a target in soluble form and part ispresented in insoluble form. As the soluble part is absorbed it may helpto form a gradient in which insoluble agent replaces absorbed agent. Inone or more embodiments insoluble agent is suspended. In one or moreembodiments the suspension is homogenous. In certain embodiments theformulation is readily resuspended and homogenous on shaking. In certainembodiments the agent is soluble.

Exemplary Groups of Active Agents

Active agents, which constitute the first viscosity modulators are notsoluble or are partially soluble and all or part thereof is suspended inthe composition. It is known that every chemical compound has differentsolubility in different solvents or compositions, and therefore it isnot possible to provide a general list compounds that fulfill such adistinction. However, an active agent, as exemplified in the listsbelow, is suitable as a first viscosity modulator according to thepresent invention if it is not soluble or is partially soluble or issuspended in the oleaginous composition.

Antibiotics

In the context of the present disclosure, an antibiotic agent is asubstance, that has the capacity to inhibit the growth of or to destroybacteria and other microorganisms.

In one or more embodiments, the antibiotic agent is selected from theclasses consisting beta-lactam antibiotics, aminoglycosides, ansa-typeantibiotics, anthraquinones, antibiotic azoles, antibioticglycopeptides, macrolides, antibiotic nucleosides, antibiotic peptides,antibiotic polyenes, antibiotic polyethers, quinolones, antibioticsteroides, sulfonamides, tetracycline, dicarboxylic acids, antibioticmetals including antibiotic metal ions, oxidizing agents, a periodate, ahypochlorite, a permanganate, substances that release free radicalsand/or active oxygen, cationic antimicrobial agents, quaternary ammoniumcompounds, biguanides, triguanides, bisbiguanides and analogs andpolymers thereof, naturally occurring antibiotic compounds, includingantibiotic plant oils and antibiotic plant extracts and any one of thefollowing antibiotic compounds including non classified antibioticcompound analogs, derivatives, salts, ions, complexes and mixturesthereof.

Tetracyclines

According to some embodiments, the antibiotic agent is a tetracycline.The tetracyclines (also referred to herein as “tetracyclineantibiotics”) are a group of antibacterials, originally derived fromcertain Streptomyces spp., having the same tetracyclic nucleus,naphthacene, and similar properties. They are usually bacteriostatic butact by interfering with protein synthesis in susceptible organisms.Tetracycline antibiotics are susceptible to degradation by oxidation.

Tetracyclines include, but are not limited to, dihydrosteffimycin,demethyltetracycline, aclacinomycin, akrobomycin, baumycin,bromotetracycline, cetocyclin, chlortetracycline, clomocycline,daunorubicin, demeclocycline, doxorubicin, doxorubicin hydrochloride,doxycycline, lymecyclin, marcellomycin, meclocycline, meclocyclinesulfosalicylate, methacycline, minocycline, minocycline hydrochloride,musettamycin, oxytetracycline, rhodirubin, rolitetracycline, rubomycin,serirubicin, steffimycin, tetracycline and analogs, salts andderivatives thereof.

Chlortetracycline, oxytetracycline, tetracycline, demeclocycline are allnatural products that have been isolated from Streptomyces spp. The morerecent tetracyclines, namely methacycline, doxycycline, and minocycline,are semisynthetic derivatives. Methacycline, like demeclocycline, has alonger half-life than tetracycline.

Tetracyclines are typically insoluble or partially soluble in manyhydrophobic solvents.

Minocycline

Minocycline is active against some tetracycline-resistant bacteria,including strains of staphylococci. Both doxycycline and minocycline aremore lipid-soluble than the other tetracyclines and they penetrate wellinto tissues. They are thus more suitable for incorporating into oily oremollient containing formulations. However, they have a place in thetreatment of chlamydial infections, rickettsial infections such astyphus and the spotted fevers, mycoplasmal infections such as atypicalpneumonia, pelvic inflammatory disease, Lyme disease, brucellosis,tularaemia, plague, cholera, periodontal disease, and acne. Thetetracyclines have also been useful in the treatment ofpenicillin-allergic patients suffering from venereal diseases,actinomycosis, bronchitis, and leptospirosis. Minocycline may sometimesbe used in multidrug regimens for leprosy. Doxycycline may be used forthe treatment and prophylaxis of malaria; it is also used in themanagement of anthrax.

In an embodiment the active ingredient may be any one of the followingnon limiting examples chlortetracycline, demeclocycline, doxycycline,lymecycline, meclocycline, methacycline, minocycline, oxytetracycline,rolitetracycline, tetracycline. In a preferred embodiment they aredoxycyline or minocycline.

Tetracycline antibiotics can be incorporated into the formulations ofthe present invention to treat, ameliorate or prevent a multitude ofdisorders responsive to tetracycline antibiotics. The formulations canbe applied topically to the skin or to the genitals or to mucosalmembranes and on and around the eye, sub-gingival and can be appliedinto a wide range of body cavities, including aural, digestive, oral,nasal, urethra, penal, endocervical, rectum, respiratory, and vaginaland tooth pocket. Non limiting examples of applications include eyeinfections, blepharitis, dry eye, inclusion conjunctivitis, glaucoma,inflammatory ocular conditions where bacterial infection or a risk ofbacterial ocular infection exists, neuropathic atrophy (in diabetes),abrasions, injuries, wounds, burns, ulcers, pyoderma, furunculosis,granuloma inguinale, periodontitis, rosacea, post-operation infectionsand tissue reconstruction, trachoma, lymphogranuloma venereum, granulomainquinale, acne, inflammation, sinusitis, neuro-protection, washing out,disinfectation, and stabilization of body cavities, at on around or inthe site of an operation, which for example can provide multipletherapeutic effects, such as, inhibition of post operation adhesions,anti infection, neuro-protection.

Whether delivered as a foam, gel, ointment or suspension the activepharmaceutical tetracycline can be present by weight in the range ofabout 0.01% to about 20%, about 0.2% to about 20%, or at about 0.01%, atabout 0.1%, at about 0.2%, at about 0.3%, at about 0.4%, at about 0.5%,at about 0.6%, at about 0.7%, at about 0.8%, at about 0.9%, at about 1%,at about 1.5%, at about 2%, at about 2.5%, at about 3%, at about 3.5% atabout 4%, at about 4.5%, at about 5%, at about 6%, at about 7%, at about8%, at about 9%, at about 10%, at about 12%, or at about 14%, at about16%, at about 18%, or at about 20%.

Tetracyclines and Skin Infections

Tetracyclines have been used in ophthalmic ointments for the preventionor treatment of infections of the eye caused by susceptible bacteria.Although minor skin infections and wounds usually heal withouttreatment, some minor skin wounds do not heal without therapy and it isimpossible to determine at the time of injury which wounds will beself-healing. Therefore, some experts believe that, by reducing thenumber of superficial bacteria, topical anti-infectives are useful forpreventing infection in minor skin injuries (e.g., cuts, scrapes,burns).

Tetracycline hydrochloride may be used topically in the prevention ortreatment of inflammatory acne vulgaris. Tetracyclines are usuallybacteriostatic in action, but may be bactericidal in high concentrationsor against highly susceptible organisms.

Tetracyclines appear to inhibit protein synthesis in susceptibleorganisms primarily by reversibly binding to 30S ribosomal subunits,thereby inhibiting binding of aminoacyl transfer-RNA to those ribosomes.In addition, tetracyclines appear to reversibly bind to 50S ribosomalsubunits. There is preliminary evidence that tetracyclines also altercytoplasmic membranes of susceptible organisms resulting in leakage ofnucleotides and other intracellular components from the cell. At highconcentrations, tetracyclines also inhibit mammalian protein synthesis.

The exact mechanisms by which tetracyclines reduce lesions of acnevulgaris have not been fully elucidated; however, the effect appears tobe partly the result of the antibacterial activity of the drugs.Following topical application to the skin of a 0.22% solution oftetracycline hydrochloride in a vehicle containing n-decyl methylsulfoxide (Topicycline®; no longer commercially available in the US),the drug inhibits the growth of susceptible organisms (principallyPropionibacterium acnes) on the surface of the skin and reduces theconcentration of free fatty acids in sebum. The reduction in free fattyacids in sebum may be an indirect result of the inhibition oflipase-producing organisms which convert triglycerides into free fattyacids or may be a direct result of interference with lipase productionin these organisms. Free fatty acids are comedogenic and are believed tobe a possible cause of the inflammatory lesions (e.g., papules,pustules, nodules, cysts) of acne. However, other mechanisms also appearto be involved because clinical improvement of acne vulgaris withtopical tetracyclines does not necessarily correspond with a reductionin the bacterial flora of the skin or a decrease in the free fatty acidcontent of sebum. (Martindale Electronic Version 2007).

Tetracyclines, Solubility and Stability

Tetracyclines are known to be unstable in the presence of water, as wellas numerous types of formulation excipients, such as protic solvents,various surfactants and certain oils. It was surprisingly discovered inU.S. Provisional Application No. 61/248,144 filed Oct. 2, 2009 andtitled “Surfactant-Free Water-Free Foamable Compositions, BreakableFoams And Their Uses,” and to U.S. Provisional Application No.61/322,148 filed Apr. 8, 2010 and titled “Surfactant-Free Water-FreeFoamable Compositions, Breakable Foams And Gels And Their Uses,” thatthe inclusion of tetracyclines in a composition comprising a hydrophobicsolvent and a foamer complex described therein results in a stableproduct, with extended stability of the tetracycline. In an embodiment ahydrophobic solvent is selected by (1) testing the solubility of saidactive agent in various hydrophobic solvents, (2) identifying those thatdo not solubilize the active agent followed by (3) inclusion in thecomposition of such solvents that do not solubilize the active agent. Inpreferred embodiments the tetracycline is insoluble in the composition.

Doxycyline

According to some embodiments, the tetracycline is doxycycline.Doxycycline is a tetracycline antibiotic and also has anti-inflammatoryand immunomodulatory effects. Doxycycline is a semisynthetictetracycline antibiotic derived from oxytetracycline. In addition toantimicrobial activity, the drug has anti-inflammatory andimmunomodulatory effects. It is available as Doxycycline calcium,doxycycline hyclate and doxycycline monohydrate. Doxycycline hyclate anddoxycycline monohydrate occur as yellow, crystalline powders. Thehyclate is soluble in water and slightly soluble in alcohol; themonohydrate is very slightly soluble in water and sparingly soluble inalcohol. Doxycycline calcium is formed in situ during the manufacturingprocess. Following reconstitution of doxycycline hyclate powder for IVadministration with sterile water for injection, solutions have a pH of1.8-3.3.

The mechanism(s) by which doxycycline reduces inflammatory lesions(papules and pustules) in patients has not been elucidated, but theseeffects may result at least in part from the anti-inflammatory actionsof the drug; other mechanisms may be involved

Doxycycline is used for the treatment of rosacea treatment orprophylaxis of anthrax (including inhalational anthrax [postexposure]),treatment of presumed or confirmed rickettsial infections, includingRocky Mountain spotted fever (RMSF), fever, ehrlichiosis, andanaplasmosis, and for the treatment of Bartonella infections, for thetreatment of brucellosis, for the treatment of Burkholderia Infections,Chlamydial Infections, Lymphogranuloma venereum Psittacosis,Ehrlichiosis and Anaplasmosis, Gonorrhea and Associated Infections,Epididymitis, Proctitis, Granuloma Inguinale (Donovanosis,) LegionellaInfections, Leptospirosis, Lyme Disease, Prophylaxis of Lyme Disease,Erythema Migrans, Early Neurologic Lyme Disease, Lyme Carditis, orBorrelial Lymphocytoma, Lyme Arthritis, Malaria, and prevention,Mycobacterial Infections, Mycobacterium marinum Infections, PelvicInflammatory Disease, Parenteral Regimens, Plague, pleural Effusion,Rickettsial Infections, Q Fever, Syphilis, Tularemia, Treatment,Postexposure Prophylaxis

When reconstituted and diluted with 0.9% sodium chloride or 5% dextrose,doxycycline hyclate IV solutions containing 0.1-1 mg of doxycycline permL are stable for 48 hours at 25° C.; when reconstituted and dilutedwith Ringer's, 10% invert sugar, Normosol-M® in D5W, Normosol-R® in D5W,Plasma-Lyte® 56 in 5% dextrose, or Plasma-Lyte® 148 in 5% dextrose,doxycycline hyclate IV solutions containing 0.1-1 mg/mL are stable for12 hours at room temperature. The manufacturer states that doxycyclinehyclate solutions prepared with any of these infusion solutions arestable for 72 hours at 2-8° C. when protected from direct sunlight andartificial light; however, after storage in this manner, infusion ofthese solutions must be completed within 12 hours Doxycycline hyclate IVsolutions diluted to a concentration of 0.1-1 mg/mL with lactatedRinger's injection or 5% dextrose in lactated Ringer's injection must beinfused within 6 hours to ensure stability. During infusion, alldoxycycline hyclate IV solutions must be protected from direct sunlight.(Martindale 2007 Electronic Version). Thus it can be seen thatDoxycycline is not stable for more than short periods of a matter ofhours.

Preparations of doxycycline hyclate have an acid pH and incompatibilitymay reasonably be expected with alkaline preparations or with drugsunstable at low pH.

Doxycycline is more active than tetracycline against many bacterialspecies including Streptococcus pyogenes, enterococci, Nocardia spp.,and various anaerobes. Cross-resistance is common although sometetracycline-resistant Staphylococcus aureus respond to doxycycline.Doxycycline is also more active against protozoa, particularlyPlasmodium spp.

Doxycycline is a tetracycline derivative with uses similar to those oftetracycline. It may sometimes be preferred to other tetracyclines inthe prevention or treatment of susceptible infections because of itsfairly reliable absorption and its long half-life that permits lessfrequent (often once daily) dosing. It also has the advantage that itcan be given (with care) to patients with renal impairment. However,relatively high doses may need to be given for urinary-tract infectionsbecause of its low renal excretion.

For relapsing fever and louse-borne typhus, for the prophylaxis ofleptospirosis, for periodontiti, for Lymphatic filariasis, forMusculoskeletal and joint disorders and for the treatment of acne.

Minocycline

According to some embodiments, the tetracycline is minocycline.Minocycline hydrochloride is a semisynthetic tetracycline antibioticderived from tetracycline. The drug is usually bacteriostatic in action;it exerts its antimicrobial activity by inhibiting protein synthesis. Itis a yellow crystalline powder that is sparingly soluble in water;slightly soluble in alcohol; practically insoluble in chloroform and inether; soluble in solutions of alkali hydroxides and carbonates. pH of asolution in water containing the equivalent of minocycline 1% is between3.5 and 4.5. Preparations of minocycline hydrochloride have an acid pHand incompatibility may reasonably be expected with alkalinepreparations or with drugs unstable at low pH.

Minocycle is highly sensitive and should be stored in airtightcontainers and protected from light to prevent degradation. Thereforeuse in foamable formulations stored in airtight sealed containers underpressure with propellant may contribute to preserving stability subjectto selection of compatible canisters and accessories.

Photosensitivity, manifested as an exaggerated sunburn reaction on areasof the body exposed to direct sunlight or ultraviolet light, hasoccurred with tetracyclines and Minocycline has been associated withpigmentation of the skin and other tissues.

Minocycline has a spectrum of activity and mode of action similar tothat of tetracycline but it is more active against many speciesincluding Staphylococcus aureus, streptococci, Neisseria meningitidis,various enterobacteria, Acinetobacter, Bacteroides, Haemophilus,Nocardia, and some mycobacteria, including M. leprae. Partialcross-resistance exists between minocycline and other tetracyclines butsome strains resistant to other drugs of the group remain sensitive tominocycline, perhaps because of better cell-wall penetration.Minocycline is a tetracycline derivative with uses similar to those oftetracycline. It is also a component of multidrug regimens for thetreatment of leprosy and has been used in the prophylaxis ofmeningococcal infection to eliminate the carrier state, but the highincidence of vestibular disturbances means that it is not the drug ofchoice for the latter. It has neuroprotective properties. It is beinginvestigated for motor neurone disease, for the management ofHuntington's chorea. It is used in the treatment of rheumatoid arthritisand in the prevention or treatment of various skin disorders, includingacne.

Steroids

In an embodiment, the active agent is a steroid. In certain embodimentsthe steroid is a corticosteroid, including but not limited to,hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone,dexamethasone-phosphate, beclomethsone dipropionate, clobetasolvalemate, desonide, desoxymethasone, desoxycorticosterone acetate,dexamethasone, dichlorisone, diflorasone diacetate, diflucortolonevalerate, fluadrenolone, fluclorolone acetonide, fludrocortisone,flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortinebutylester, fluocortolone, fluprednidene (fluprednylidene) acetate,flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisonebutyrate, methylprednisolone, triamcinolone acetonide, cortisone,cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate,fluradrenolone acetonide, medrysone, amcinafel, amcinafide,betamethasone and the balance of its esters, chloroprednisone,chlorprednisone acetate, clocortelone, clescinolone, dichlorisone,difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone,fluprednisolone, hydrocortisone valerate, hydrocortisonecyclopentylpropionate, hydrocortmate, mepreddisone, paramethasone,prednisolone, prednisone, beclomethasone dipropionate, triamcinolone, aswell as analogs, derivatives, salts, ions and complexes thereof.

Many steroids are typically insoluble or partially soluble in varioushydrophobic solvents.

In certain embodiments, the steroid is a hormone or a vitamin or ananti-infective agent, as exemplified by pregnane, cholestane, ergostane,aldosterone, androsterone, calcidiol, calciol, calcitriol, calcipotriol,clomegestone, cholesterol, corticosterone, cortisol, cortisone,dihydrotestosterone, ergosterol, estradiol, estriol, estrone,ethinylestradiol, fusidic acid, lanosterol, prednisolone, prednisone,progesterone, spironolactone, timobesone and testosterone, as well asanalogs, derivatives, salts, ions and complexes thereof. For substanceslike calcitriol, very low amounts such as about 0.0001% to about 0.005%by weight of foam formulation or gel or ointment or suspension, or about0.0001%, about 0.0002%, about 0.0003%, about 0.0004%, about 0.0005%,about 0.0006%, about 0.0007%, about 0.0008%, about 0.0009%, about0.001%, about 0.0011%, about 0.0012%, about 0.0013%, about 0.0014%,about 0.0015%, about 0.0016%, about 0.0017%, about 0.0018%, about0.0019%, about 0.002%, about 0.003%, about 0.004%, about 0.005% byweight are effective. In some embodiments the active pharmaceuticalagent is delivered by more than one route, for example, topically andbody cavity.

In an embodiment, the steroid is mometasone furoate. In certainembodiments it can be used topically to treat psoriasis and dermatitis.In certain other embodiments it can be applied in nasal administrationto treat disorders, such as, allergic rhinitis and asthma.

NSAID

In an embodiment, the active agent is a non-steroidal anti-inflammatoryagent. In the context a nonsteroidal antiinflammatory agent (also termedherein “NSAID”) is a pharmaceutically active compound, other than acorticosteroid, which affects the immune system in a fashion thatresults in a reduction, inhibition, prevention, amelioration orprevention of an inflammatory process and/or the symptoms ofinflammation and/or the production pro-inflammatory cytokines and otherpro-inflammatory mediators, thereby treating or preventing a diseasethat involves inflammation.

In one or more embodiments, the NSAID is an inhibitor of thecyclooxygenase (COX) enzyme. Two forms of cyclooxygenase are knowntoday: the constitutive cyclooxygenase (COX-1); and the induciblecyclooxygenase (COX-2), which is pro-inflammatory. Thus, in one or moreembodiments, the NSAID is selected from the group consisting of a COX-1inhibitor, a COX-2 inhibitor or a non-selective NSAID, whichsimultaneously inhibits both COX-1 and COX-2.

In one or more embodiments, the NSAID is salicylic acid a salicylic acidderivatives. Exemplary salicylic acid derivative include, in a nonlimiting fashion, aspirin, sodium salicylate, choline magnesiumtrislicylate, salsalate, diflunisal, salicylsalicylic acid,sulfasalazine, olsalazine, esters of salicylic acid with a carboxylicacid, esters of salicylic acid with a dicarboxylic acid, esters ofsalicylic acid with a fatty acid, esters of salicylic acid with ahydroxyl fatty acid, esters of salicylic acid with an essential fattyacid, esters of salicylic acid with a polycarboxylic acid, and anycompound wherein salicylic acid is linked to an organic moiety through acovalent bond.

In one or more embodiments, the NSAID is para-aminophenol (e.g.,acetaminophen) and salts and derivatives thereof.

In one or more embodiments, the NSAID is an indole or an indole-aceticacid derivative (e.g., indomethacin, sulindac, etodolac) and salts andderivatives thereof.

In one or more embodiments, the NSAID is an aryl acetic acids (e.g.,tolmetin, diclofenac, ketorolac) and salts and derivatives thereof.

In one or more embodiments, the NSAID is an arylpropionic acid and saltsand derivatives thereof. Exemplary arylpropionic acid derivativeinclude, in a non limiting fashion, are ibuprofen, naproxen,flubiprofen, ketoprofen, fenoprofen, oxaprozin.

In one or more embodiments, the NSAID is anthranilic acids or ananthranilic acid derivative, also termed “fenamates” (e.g., mefenamicacid, meclofenamic acid) and salts and derivatives thereof.

In one or more embodiments, the NSAID is selected from the group ofenolic acids, enolic acid salts, enolic acid esters, amides, anhydridesand salts and derivatives thereof. Non-limiting examples of enolic acidderivatives include oxicams (piroxicam, tenoxicam) andpyrazolidinediones (phenylbutazone, oxyphenthratrazone)

Yet, in additional embodiments, the NSAID is an alkanone (e.g.,nabumetone).

Selective COX-2 Inhibitors include, in an exemplary mannerdiaryl-substituted furanones (e.g., Rofecoxib); diaryl-substitutedpyrazoles (e.g., Celecoxib); indole acetic acids (e.g., Etodolac); andsulfonanilides (e.g., Nimesulide) and salts and derivatives thereof.

Many NSAIDs are typically insoluble or partially soluble in hydrophobicsolvents.

Local Anesthetic Agents

In an embodiment, the active agent is a local anesthetic agent. Withoutlimiting the scope, the anesthetic agent can be selected from the groupconsisting of benzocaine, lidocaine, bupivacaine, chlorprocaine,dibucaine, etidocaine, mepivacaine, tetracaine, dyclonine, hexylcaine,procaine, cocaine, ketamine, pramoxine, phenol, any pharmaceuticallyacceptable salts thereof and mixtures of such anesthetic agents. Anymixture of synergistically beneficial anesthetic agents is contemplated.

Keratolytically Active Agents

A keratolytic agent may be included as an active agent of thecomposition. The term “keratolytically active agent” as used hereinincludes a compound that loosens and removes the stratum corneum of theskin, or alters the structure of the keratin layers of skin.Keratolytically active agents are used in the prevention or treatment ofdermatological disorders that involve dry skin, hyperkeratinization(such as psoriasis), skin itching (such as xerosis), acne and rosacea.

Suitable keratolytically active agents include phenol and substitutedphenolic compounds. Such compounds are known to dissolve and loosen theintracellular matrix of the hyperkeratinized tissue. As such, they areused in the prevention or treatment of dermatological disorders.Dihydroxybenzene and derivatives thereof have been recognized as potentkeratolytic agents. Resorcinol (m-dihydroxybenzene) and derivativesthereof are used in anti-acne preparations. In addition to hydroquinone(p-dihydroxybenzene) having anti-pigmentation properties, hydroquinoneis also known to be keratolytic. These compounds also exhibit antisepticproperties. Cresols also possess bactericidal and keratolyticproperties.

Vitamin A and vitamin A derivatives, also termed herein “retinoids”,such as retinoic acid, isoretinoic acid, retinol and retinal, as well asadapalene, tazarotene, isotretinoin, acitretin and additional retinoidsknown in the art of pharmaceuticals and cosmetics are another class ofkeratolytically active agents.

Another group of keratolytically active agents include alpha-hydroxyacids, such as lactic acid and glycolic acid and their respective saltsand derivatives; and beta-hydroxy acids, such as salicylic acid(o-hydroxybenzoic acid) and salicylic acid salts and pharmaceuticallyacceptable derivatives.

Another class of keratolytically active agents includes urea and ureaderivatives.

Immunomodulators

In an embodiment, the active agent is an immunomodulator.Immunomodulators are chemically or biologically-derived agents thatmodify the immune response or the functioning of the immune system.Immunomodulators suitable for use according to the present inventioninclude, among other options, cyclic peptides, such as cyclosporine,tacrolimus, tresperimus, pimecrolimus, sirolimus, verolimus, laflunimus,laquinimod and imiquimod, as well as analogs, derivatives, salts, ionsand complexes thereof. Such compounds, delivered in the foam, areespecially advantageous in skin disorders such as psoriasis, eczema andatopic dermatitis, where the large skin areas are to be treated.

Retinoids

In an embodiment, the active agent is a retinoid. Retinoids suitable foruse according to the present invention include, among other options,retinol, retinal, retinoic acid, isotretinoin, tazarotene, adapalene,13-cis-retinoic acid, acitretin all-trans beta carotene, alpha carotene,lycopene, 9-cis-beta-carotene, lutein and zeaxanthin, as well as anyadditional retinoids known in the art of pharmaceuticals and cosmetics;and analogs, derivatives, salts, ions and complexes thereof.

Anti-Acne and Anti-Rosacea Active Agents

In an embodiment, the active agent is an anti-acne or an anti-rosaceaagent. The anti-acne agent can be selected from the group consisting ofresorcinol, sulfur, salicylic acid and salicylates, alpha-hydroxy acids,nonsteroidal anti-inflammatory agents, benzoyl peroxide, retinoic acid,isoretinoic acid and other retinoid compounds, adapalene, tazarotene,azelaic acid and azelaic acid derivatives, antibiotic agents, such aserythromycin and clyndamycin, coal tar, zinc salts and complexes, andcombinations thereof, in a therapeutically effective concentration.

Antipsoriasis Agents

In an embodiment, the active agent is an anti-psoriasis agent. Suchanti-psoriasis agents can be selected, among other options, from thegroup of keratolytically-active agents, salicylic acid, coal tar,anthralin, corticosteroids, vitamin D and derivatives and analogsthereof, including vitamin D3 analogs such as calcitriol, calcipotriol;retinoids, and photodynamic therapy agents.

Antiinfective Agents

In an embodiment, the active agent is an anti-infective agent. Suchanti-infective agent can be selected from the group of an antibioticagent, an antibacterial agent, an antifungal agent, an agent thatcontrols yeast, an antiviral agent and an antiparasitic agent. Exemplaryantiinfective agents are exemplified by beta-lactam antibiotic, anaminoglycoside, an ansa-type antibiotic, an anthraquinone, an azole,metronidazole, an antibiotic glycopeptide, a macrolide, erythromycin,clindamycin, an antibiotic nucleoside, an antibiotic peptide, polymyxinB, an antibiotic polyene, an antibiotic polyether, an antibioticquinolone, an antibiotic steroid, fucidic acid, mupirocin,chloramphenicol, a sulfonamide, tetracycline, an antibiotic metal,silver, copper, zinc, mercury, tin, lead, bismuth, cadmium, chromium, anoxidizing agent, iodine, iodate, a periodate, a hypochlorite, apermanganate, a substance that release free radicals and/or activeoxygen, a cationic antimicrobial agent, a quaternary ammonium compound,a biguanide, chlorohexidine, a triguanide, a bisbiguanide, a polymericbiguanide and a naturally occurring antibiotic compound, as well asanalogs, derivatives, salts, ions and complexes thereof.

The Composition Essential Ingredients as Active Agents

In certain embodiments, a hydrophobic solvent possesses therapeuticproperties on its own and therefore, it can be regarded as “activeagent.” For example, some essential oils kill microorganisms and can beeffective in the treatment or prevention of conditions that involvemicrobial infection, such as bacterial, fungal and viral conditions.Additionally, the occlusive effect of hydrophobic solvents is useful forthe treatment of conditions which involve damaged skin, such aspsoriasis or atopic dermatitis. The combination of a hydrophobic solventand a therapeutically effective fatty alcohol or fatty acid may afford asynergistic beneficial effect in conditions characterized, for example,by infection and/or inflammation.

Combination of Active Agents

Several disorders involve a combination of more than one etiologicalfactor; and therefore, the use of more that one active agents isadvantageous. For example, psoriasis involves excessive cellproliferation and inadequate cell differentiation as well asinflammation. Atopic dermatitis involves keratinocyte growthabnormality, skin dryness and inflammation. Bacterial, fungal and viralinfections involve pathogen colonization at the affected site andinflammation. Hence, in many cases, the inclusion of a combination ofactive agents in the pharmaceutical composition can be desirable. Thus,in one or more embodiments, the composition further includes at leasttwo active agents, in a therapeutically effective concentration.

In an embodiment one of the active agents is a vitamin, a vitaminderivative or analogue thereof. In a preferred embodiment the vitamin,vitamin derivative or analogue thereof is oil soluble.

Microsponges

Microsponges (or microspheres) are rigid, porous and sponge-like roundmicroscopic particles of cross-linked polymer beads (e.g., polystyreneor copolymers thereof), each defining a substantially non-collapsiblepore network. Microsponges can be loaded with an active ingredient andcan provide a controlled time release of the active ingredient to skinor to a mucosal membrane upon application of the formulation. The slowrelease is intended to reduce irritation by the active. Microsponge®delivery technology was developed by Advanced Polymer Systems. In one ormore embodiments the composition comprises one or more active agentsloaded into Microsponges with a waterless carrier described herein,which may also comprise a modulating agent.

Fields of Applications

The carrier of the present disclosure is suitable for treating anyinflicted surface or preventing onset of an anticipated disorder ordisease or for achieving a period of remission. In one or moreembodiments, carrier is suitable for administration to the skin, a bodysurface, a body cavity or mucosal surface, e.g., the cavity and/or themucosa of the nose, mouth, eye, respiratory system, vagina, urethra,rectum and the ear canal (severally and interchangeably termed herein“target site”).

The foamable carrier of the present disclosure is also suitable forpreventing a disorder or disease prior to its onset. The foamablecomposition comprising for example a tetracycline may be applied to abody surface or a body cavity to try and prevent apoptosis, a disorderor disease prior to onset thereof. For example, prior to an anticipatedinflammatory reaction or risk thereof, or prior to an anticipated onsetof apoptosis or a risk thereof, or prior to an anticipated onset ofinflammatory cytokines or risk thereof, prior to a medical procedurerequiring intervention such as chemotherapy; radiotherapy, photodynamictherapy, laser therapy, etc. In an embodiment the composition is appliedto prevent or reduce the risk of spreading.

According to an embodiment a none limiting of list of disorders where atetracycline antibiotic might be used to prevent a disease or disorderincludes prophylaxis of gonococcal and chlamydial ophthalmia, neonatalconjunctivitis, periodontal disease, postoperative tetracycline,prophylaxis in pregnancy termination, for prevention of skinrash/acneiform skin eruption during cancer therapy, intraoperativetopical tetracycline sclerotherapy following mastectomy for preventionof postoperative mastectomy seromas etc.

By selecting a suitable active agent, or a combination of at least twoactive agents, the composition of the present disclosure is useful inalleviating or treating an animal or a human patient having oranticipated to have any one of a variety of dermatological diseases ordisorders, or where such agent or agents have shown proficiency inpreventative therapy in preventing such diseases or disorders,including, but not limited to a bacterial infection, a benign tumor, abullous disease, a burn, a chlamydia infection, a condition whichrespond to hormone therapy, a cut, a dermatitis, a dermatophyteinfection, a dermatose, a disorder of a body cavity, a disorder ofcornification, a disorder of the nose, a disorder of the penile urethraor ear canal, a disorder of the rectum, a disorder of the respiratorysystem, a disorder of the vagina, a disorder which responds to hormonereplacement therapy, a disorder which responds to transdermal nicotineadministration, a disorders of hair follicles, a disorders of sebaceousglands, a disorders of sweating, a fungal infection, a gonorrheainfection, a gynecological disorders that respond to hormonal therapy, amalignant tumor, a non-dermatological disorder which responds to topicalor transdermal delivery of an active agent, a parasitic infection, apelvic inflammation, a pigmentation disorder, a scaling papulardiseases, a sexual dysfunction disorder, a sexually transmitted disease,a vaginal disorder, a viral infection, a vulvar disorder, a vulvovaginalinfection, a wound, a yeast infection, abscess, acne, acne conglobata,acne fulminans, acne scars, acne vulgaris, actinic keratosis, acute andchronic salpingitis, acute febrile neutrophilic dermatosis, acutelymphangitis, acute pelvic inflammatory disease, acute soft tissueinjury, albinism, allergic contact dermatitis, alopecia, alopeciaareata, alopecia totalis, alopecia universalis, an allergy, an analabscess or fistula, an anal and rectal disease, an anal disorder, ananal fissure, an anal wart, an ear disorder, an hormonal disorder, aninflammatory reaction, an intra-vaginal or rectal sexually-transmittedand non-sexually-transmitted infectious disease, anal cancer, analexcoriation, anal fissures, anal itch, anal pruritus, anal soreness,anal warts, angiomas, arthritis, athlete's foot, atopic dermatitis, backpain, bacterial skin infections, bacterial vaginosis, baldness, basalcell carcinoma, benign tumors, blisters, bromhidrosis, bullous diseases,bullous pemphigoid, burn, calluses, calluses candidiasis, cancer of thecervix, cancer of the vagina, cancer of the vulva, candidal vaginitis,candidiasis, carbuncles, cellulitis, cervical cancer, cervicitis,chancroid, chemical burns, chicken pox, chloasma, cholesteatoma,cholinergic urticaria, chronic dermatitis, chronic effects of sunlight,cold sores, cold urticaria, comedones, constipation, contact dermatitis,corns, creeping eruption, Crohn's disease, cutaneous abscess, cutaneouslarva migrans, cutaneous myiasis, dark spots, delusional parasitosis,Dercum disease, dermatitis, dermatitis herpetiformis, dermatofibroma,dermatological inflammation, dermatological pain, dermatophytoses,dermographism, diaper rash, drug eruptions and reactions, drug-inducedhyperpigmentation, dyshidrotic eczema, dysmenorrhea, dyspareunia,dysplastic nevi, ecthyma, ectodermal dysplasia, ectopic pregnancy,eczema, endometriosis, endometritis, epidermal necrolysis, epidermoidcyst, erysipelas, erythema multiforme, erythema nodosum, erythrasma,exfoliative dermatitis, fallopian tube cancer and gestationaltrophoblastic disease, fecal incontinence, female orgasmic disorder,folliculitis, fungal nail infections, fungal skin infections, furuncles,gangrene, generalized exfoliative dermatitis, genital cancer, genitalherpes, genital ulcer, genital warts, granuloma annulare, granulomainguinale, gynecological neoplasms including endometrial cancer, headlice, hemorrhoids, hepatitis B, herpes, herpes simplex, hidradenitissuppurativa, hirsutism, HIV/AIDS, hives, human papillomavirus (HPV),hyperhidrosis, hyperpigmentation melasma, hypertrichosis, hypohidrosis,hypopigmentation, ichthyosis, impetigo, inflammatory acne, inflammatoryreactions, ingrown nails, intertrigo, irritant contact dermatitis,ischemic necrosis, itching, jock itch, joint pain, Kaposi's sarcoma,keloid, keratinous cyst, keratoacanthoma, keratosis pilaris, lichenplanus, lichen sclerosus, lichen simplex chronicus, linearimmunoglobulin A disease, lipomas, localized pain in general,lymphadenitis, lymphangitis, lymphogranloma venereum, male patternbaldness, malignant melanoma, malignant tumors, mastocytosis, measles,melanoma, midcycle pain, midcycle pain due to ovulation, miliaria,mittelschmerz, moles, molluscum contagiosum, MRSA, mucopurulentcervicitis (MPC), muscle pain, necrotizing fasciitis, necrotizingmyositis, necrotizing subcutaneous infection, necrotizing subcutaneousinfections, nodular papulopustular acne, nongonococcal urethritis (NGU),non-inflammatory acne, nummular dermatitis, oophoritis, oral herpes,osteoarthritis, ostheoarthritis, ovarian cancer, ovarian cysts andmasses, paget's disease of the nipples, panniculitis, papules,parapsoriasis paronychia, parasitic infections, parasitic skininfections, paronychial infection, pediculosis, pelvic congestionsyndrome, pelvic inflammatory disease, pelvic pain, pemphigus, perianalpruritus, perianal thrush, perioral dermatitis, photo-allergy,photo-damage, photo-irritation, photosensitivity, pigmentationdisorders, pimples, pityriasis Lichenoides, pityriasis rosea, pityriasisrubra pilaris, poison ivy, poison oak, polyps of the colon and rectum,postinflammatory hyperpigmentation, postinflammatory hypopigmentation,post-operative or post-surgical skin conditions, premenstrual syndrome,pressure sores, pressure ulcers, pressure urticaria, pruritis, pruritusani, pseudofolliculitis barbae, psoriasis, PUPPP, purpura, pustules,pyogenic granuloma, rash, reactions to sunlight, rectal abscess, rectalfistula, rheumatic pain, ringworm, rosacea, roseola, rubella,salpingitis, scabies, scalded skin syndrome, scaling papular diseases,scarring, scleroderma, sebaceous cyst, seborrheic dermatitis, seborrheickeratoses, seborrheic keratosis, sexual arousal disorder, shingles, skinaging, skin cancer, skin neoplasia, skin neoplasms, skin rash, skintags, skin ulcers, sports injuries, squamous cell carcinoma,staphylococcal scalded skin syndrome, stasis dermatitis, Stevens-Johnsonsyndrome, sun spots, sunburn, thermal burns, tinea corporis, tineacruris, tinea pedis, tinea versicolor, toxic epidermal necrolysis,trauma or injury to the skin, trichomonas vaginalis, trichomoniasis,vaginal cancer, vaginal dryness, vaginismus, varicella zoster virus,viral skin infections, vitamin D deficiency, vitiligo, vulvar cancer,vulvar disorders, vulvar dystrophy, vulvar intraepithelial neoplasia(VIN), vulvar pain, vulvodynia, warts, water hives, wrinkles, xerosis,yeast skin infections, zoster.

Likewise, the composition of the present disclosure is suitable forpreventing or treating or alleviating a disorder or anticipated disorderof a body cavity or mucosal surface, e.g., the mucosa of the nose,mouth, eye, ear, respiratory system, vagina, urethra, or rectum. Nonlimiting examples of such conditions include chlamydia infection,gonorrhea infection, hepatitis B, herpes, HIV/AIDS, human papillomavirus(HPV), genital warts, bacterial vaginosis, candidiasis, chancroid,granuloma Inguinale, lymphogranloma venereum, mucopurulent cervicitis(MPC), molluscum contagiosum, nongonococcal urethritis (NGU),trichomoniasis, vulvar disorders, vulvodynia, vulvar pain, yeastinfection, vulvar dystrophy, vulvar intraepithelial neoplasia (VIN),contact dermatitis, pelvic inflammation, endometritis, salpingitis,oophoritis, genital cancer, cancer of the cervix, cancer of the vulva,cancer of the vagina, vaginal dryness, dyspareunia, anal and rectaldisease, anal abscess/fistula, anal cancer, anal fissure, anal warts,Crohn's disease, hemorrhoids, anal itch, pruritus ani, fecalincontinence, constipation, polyps of the colon and rectum.

In an embodiment of the present disclosure, the composition is usefulfor the treatment of an infection. In one or more embodiments, thecomposition is suitable for the treatment or prevention of an infection,selected from the group of a bacterial infection, a fungal infection, ayeast infection, a viral infection and a parasitic infection.

In an embodiment of the present disclosure, the composition is usefulfor the treatment of wound, ulcer and burn. This use is particularlyimportant since the composition of the present disclosure creates athin, semi-occlusive layer, which coats the damaged tissue, whileallowing exudates to be released from the tissue.

The composition of the present disclosure is also suitable foradministering a hormone to the skin or to a mucosal membrane or to abody cavity, in order to deliver the hormone into the tissue of thetarget organ, in any disorder that responds to treatment with a hormone.

In one embodiment the disorder is an inflammation, skin inflammation,acne, rosacea, actinic keratosis, skin cancer, a local pain, joint painand ostheoarthritis; the active agent is a nonsteroidalanti-inflammatory drug, given at a therapeutically effectiveconcentration.

In light of the hygroscopic nature of the composition, it is furthersuitable for the treatment and prevention of post-surgical adhesions.Adhesions are scars that form abnormal connections between tissuesurfaces. Post-surgical adhesion formation is a natural consequence ofsurgery, resulting when tissue repairs itself following incision,cauterization, suturing, or other means of trauma. When comprisingappropriate protective agents, the foam is suitable for the treatment orprevention of post surgical adhesions. The use of foam is particularlyadvantageous because foam can expand in the body cavity and penetrateinto hidden areas that cannot be reached by any other alternative meansof administration.

Cosmetic Use

In one or more embodiments, the composition may be used for cosmeticuse. For example it may be used as part of a cosmetic formulation toprevent a cosmetic disorder or to improve the skin. Alternatively it maybe used with cosmetic effect for example as a cosmetic remover. It canbe dispensed in small quantities targeted to a surface and appliedlocally with mechanical force causing the foam or gel to break.

Route of Administration

In one or more embodiments the formulations are prepared withoutpropellant and are applied as a gel or ointment, for example, with thetetracycline as a suspension. Alternatively, in one or more embodimentsthe formulations are prepared with a propellant and are applied as afoam.

In one or more embodiments, the gel is capable of forming a foamablecomposition when packaged into an aerosol canister, equipped with avalve and pressurized with a liquid or pressurized gas propellant and iscapable of releasing a foam of quality that is breakable uponapplication of shear force but is not thermolabile at about or close tobody temperature (about 36° C.).

In one or more embodiments, upon addition of between about 8% to about12% propellant, the formulations 238P, 238A, 238B, 238C, 238D, 244A,244B, 244P in Examples 4, 6 and 7 provided a foam of good or excellentquality that had a collapse time in excess of 3 minutes.

Application can be hourly, 2 hourly, 3 hourly, four hourly, six hourlyor eight hourly, twelve hourly, daily, alternate-day or intermittent, asnecessary. For reasons of compliance less frequent applications, wherepossible are preferable such as twice-daily or daily singleapplications. In cases where prolonged or long term treatment isrequired a higher initial dose is provided followed by a gradualreduction to a lower maintenance dose, which can be increased if furtheroutbreaks occur.

The formulations are suitable for administration directly or indirectlyto an inflicted area, in need of treatment, through the following routesof administration:

-   -   1. Topical administration: for local effect, it is applied        directly where its action is desired;    -   2. Enteral: when the desired effect is systemic (non-local), it        is given via the digestive tract; and    -   3. Parenteral: when the desired effect is systemic, it is given        by other routes than the digestive tract

The following list more specifically exemplifies some routes ofadministration.

1. Topical

Topical administration is any form of administration that reaches a bodyorgan topically, such as epicutaneous administration (application ontothe skin), inhalation, enema, eye drops (onto the conjunctiva), eardrops, intranasal (into the nose) and vaginal.

Exemplary dosage forms that are suitable for topical administration ofthe stable tetracycline formulations include cream, gel, liniment,lotion, ointment, paste, spray, foam, mousse, lacquer (e.g., for nailtreatment) and transdermal patch. Additionally, topical vaginal dosageforms may include a douche, an intrauterine device, a pessary (vaginalsuppository), a vaginal ring and a vaginal tablet. Rectal dosage formsinclude enema and suppositories. Inhaled dosage forms include aerosolinhalers, metered dose inhalers and solutions for nebulizer. Ophthalmicdosage forms include eye drop (solution or suspension), ophthalmic geland ophthalmic ointment. In another embodiment the dosage form is a foamthat is quickly breaking (non thermally stable) or breakable under shearforce which allows comfortable application and well directedadministration to the target area.

2. Enteral

Enteral is any form of administration that involves any part of thegastrointestinal tract by mouth (orally), as buccal or sublingualtablets, capsules, suspensions, solutions, powder or drops; by gastricfeeding tube, duodenal feeding tube, or gastrostomy; and rectally, insuppository or enema form.

3. Parenteral by Injection or Infusion

Intravenous (into a vein); intraarterial (into an artery); intramuscular(into a muscle); intracardiac (into the heart); subcutaneous (under theskin); intraosseous infusion (into the bone marrow); intradermal, (intothe skin itself); intrathecal (into the spinal canal); andintraperitoneal (into the peritoneum).

4. Other Parenteral

Transdermal (diffusion through the intact skin); transmucosal (diffusionthrough a mucous membrane), e.g. insufflation (snorting), sublingual,buccal (absorbed through cheek near gumline) and vaginal; andinhalational; epidural (synonym: peridural) (injection or infusion intothe epidural space); and intravitreal.

EXAMPLES

The invention is described with reference to the following examples, ina non-limiting manner. The following examples exemplify the compositionsand methods described herein. The examples are for the purposes ofillustration only and are not intended to be limiting. Many variationswill suggest themselves and are within the full intended scope.

Example 1—General Manufacturing Procedures

The following procedures are used to produce gel and foam samplesdescribed in the examples below, in which only the steps relevant toeach formulation are performed depending on the type and nature ofingredients used.

Step 1: Hydrophobic solvent are heated to 60-70° C.

Step 2: Fatty alcohols if present, fatty acids if present, surfactantsif present are added to the hydrophobic solvent and the formulation ismixed until complete melting.

Step 3: The formulation is cooled down to 30-40° C., active ingredientsif present are added and the formulation is mixed until homogeneity isobtained.

Step 4—for Gels: The formulation is cooled down to room temperatureunder mixing and packaged into suitable containers.

Step 4—for Foams: The formulation is packaged in aerosol canisters whichare crimped with a valve, pressurized with propellant and equipped withan actuator suitable for foam dispensing. Optionally a metered dosageunit can utilized, to achieve delivery of repeatable measured doses offoam.

Materials

TABLE 1 Exemplary possible ingredients suitable for the production ofgels and/or foamable compositions disclosed herein. Equivalent materialsfrom other manufacturers can also be used satisfactorily. Chemical NameFunction Commercial Name Supplier Alpha-tocopherol AntioxidantAlpha-tocopherol Sigma-Aldrich Beeswax white Foam adjuvant Beeswax whiteHenry Lamotte Behenyl alcohol Foam adjuvant Lanette 22 Cognis Benzoylperoxide Active agent Benzoyl peroxide Spectrum BHA AntioxidantButylhydroxyanisole Merk BHT Antioxidant Butylated HydroxitolueneSpectrum C12-C15 alkyl benzoate Solvent C12-C15 alkyl benzoate FinetexCastor oil Solvent Castor oil Fluka Ceteareth-20 Surfactant Sympatensacs 200G Colb Cetearyl octanoate Solvent Luvitol EHO BASF Ceteth-2Surfactant Lipocol C-2 Lipo Cetostearyl alcohol Foam adjuvant SpeziolC16-C18 Cognis Cetyl alcohol Foam adjuvant Speziol C16 CognisCholesterol Wax Cholesterol Spectrum Cocoglycerides Solvent Novata ACognis Coconut oil Solvent Coconut oil Henry Lamotte Cyclomethicone-5Solvent ST-cyclomethicone-5 Dow Diclofenac Sodium Active agentDiclofenac Sodium Spectrum Diethylene glycol monoethyl SolventTranscutol Gattefosse ether Dimethyl Isosorbide Solvent DimethylIsosorbide Dotticon Dimethyl Sulfoxide Solvent Dimethyl Sulfoxide FlukaDiisopropyl adipate Solvent Isoadipate Symrise GmbH Doxycycline HyclateActive agent Doxycycline Hyclate Yangzhou Ethanol Absolute SolventEthanol Absolute J. T. Baker Ethylcellulose Polymer EC-Ethocel 100 cP FPColorcon Dow Gelled mineral oil Solvent Versagel M 750 Penreco PPG-20Methyl Glucose Humectant Glucam P20 Distearate Lubrizol Ether DistearateGlycerin Solvent Glycerin Cognis Glyceryl monostearate Surfactant CutinaGMS V PH Cognis Hard Fat Wax Softisan 378 Sasol Heavy Mineral OilSolvent Paraffin oil liquid heavy Gadot Hexylene Glycol Solvent HexyleneGlycol Sigma-Aldrich Hydrogenated castor oil Foam adjuvant Cutina HRCognis Isododecane Solvent AB117128 ABCR GmbH & Co. KG Isopropylmyristate Solvent Isopropyl Myristate Ph. Cognis Isostearic acid Foamadjuvant Isostearic acid Stearinerie Dubois Isostearyl alcohol SolventPrisorine 3515 Croda Lanolin Foam adjuvant Lanolin Spectrum Laureth-4Surfactant Dehydol LS 4 DEO N Cognis Light Mineral Oil Solvent Pioner2076P Hansen & Rosenthal MCT Oil Solvent Captex 355 Abitec MentholAdditive Menthol Premium Ingredients Int. Methyl glucose Surfactant TegoCare PS Evonik Goldcshmidt sesquistearate Metronidazole Active agentMetronidazole Galdetma Minocycline HCl Active agent Minocycline HClHovione Mometasone furoate Active agent Mometasone furoate Sicor deMexico Cetearyl alcohol & coconut Surfactant Montanov S Seppic alcoholMyristyl alcohol Foam adjuvant Speziol C14 Cognis Octyldodecanol SolventEutanol G Cognis Oleic acid Solvent Oleic acid Spectrum Oleth-20Surfactant Emulgin O 0 S Cognis Oleyl alcohol Solvent HD Eutanol V PHCognis Palmitic acid Foam adjuvant Edenor C16 98-100GW Cognis Paraffinwax 42-44 Wax Paraffin 42-44 Merck Paraffin wax 51-53 Wax Paraffin 51-53Merck Paraffin wax 58-62 Wax Paraffin 58-62 Merck PEG-40 Hydrogenatedcastor Surfactant Emulgin HRE 40 Cognis oil Polyethylene glycol-200Solvent PEG 200 Merck Polyethylene glycol-400 Solvent PEG 400Sigma-Aldrich PEG-75 Lanolin Surfactant SOLULAN 75 Lubrizol PEG-100Stearate Surfactant Myrj 59 P Croda PEG-150 distearate SurfactantEmulgin EO 33 Cognis Permethrin Active agent Permethrin Sigma PetrolatumCarrier Sofmetic LMP Sofmetic Pimecrolimus Active agent Pimecrolimus —PPG 15 stearyl ether Solvent Arlamol E Uniqema PPG-20-methyl glucoseether Humectant Glucam P-20 Lubrizol Propane/Isobutane/Butane PropellantA-46 Aeropress (20:78:2) Propane/Isobutane/Butane Propellant AP-70Aeropress (55:18:27) Propyl gallate Antioxidant Propyl gallateSigma-Aldrich Propylene glycol Solvent Propylene glycol Gadot Salicylicacid Active agent Salicylic acid Merck Silicon dioxide DispersantAerosil R 972 PH Evonik-Goldschmidt GmbH Sorbitan sesquistearateSurfactant Tego care PS Degussa Soybean oil Solvent Soybean oil SpectrumSorbitan monopalmitate Surfactant SPAN 40 Spectrum Sorbitan monostearateSurfactant SPAN 60 Uniqema Steareth-2 Surfactant Brij 72 SpectrumSteareth-21 Surfactant Brij 721 Spectrum Stearic acid Foam adjuvantEdenol ST1M Cognis Stearyl Alcohol Foam adjuvant Speziol C18 CognisSucrose stearic acid Surfactant Surfhope SE D1803 Mitsubishi estersD1803Sucrose stearic acid Surfactant Surfhope SE D1807 Mitsubishi estersD1807Sucrose stearic acid Surfactant Surfhope SE D1811 Mitsubishi estersD1811Sucrose stearic acid Surfactant Surfhope SE D1813 Mitsubishi estersD1813Terbinafine HCl Active agent Terbinafine HCl Taro Tetracycline HClActive agent Tetracycline HCl Xian lijun Titanium dioxide — Kemira AFDCKermira Polysorbate 20 Surfactant Tween 20 Merck Polysorbate 60Surfactant Tween 60 Merck Urea Active agent Urea Gadot Vitamin EAntioxydant Tocopherol Sigma White Petrolatum (hard) Carrier Vaselinecodex GAL Aiglon White Petrolatum (soft) Carrier Sofmetic LMF MMP1,3-Butandiol Solvent Butylene Glycol Sigma-Aldrich C12-15 Alkyl LactateEmollient C12-15 Alkyl Lactate A&E Connock

Canisters Filling and Crimping

Each aerosol canister is filled with the bulk formulation) and crimpedwith valve using vacuum crimping machine. The process of applying avacuum will cause most of the oxygen present to be eliminated. Additionof hydrocarbon propellant may, without being bound by any theory,further help to reduce the likelihood of any remaining oxygen reactingwith the active ingredient. It may do so, without being bound by anytheory, by one or more of dissolving in, to the extent present, the oilor hydrophobic phase of the formulation, by dissolving to a very limitedextent in the aqueous phase, by competing with some oxygen from theformulation, by diluting out any oxygen, by a tendency of oxygen tooccupy the dead space, and by oxygen occupying part of the space createdby the vacuum being the unfilled volume of the canister or thatremaining oxygen is rendered substantially ineffective in theformulation.

Pressurizing & Propellant Filling

Pressurizing is carried out using a hydrocarbon gas or gas mixture.Canisters are filled and then warmed for 30 seconds in a warm bath at50° C. and well shaken immediately thereafter.

By way of non-limiting example, tests are briefly set out below as wouldbe appreciated by a person of the art.

Viscosity is measured with Brookfield LVDV-II+PRO with spindle SC4-25 atambient temperature and 20, 10, 5 and/or 1 RPM. Viscosity is usuallymeasured at 10 RPM or 20 RPM. However, at about the apparent upper limitfor the spindle of ˜>50,000 CP, the viscosity at 1 RPM may be measured,although the figures are of a higher magnitude.

Chemical Stability: the amount of active agent present is analyzedchromatographically. Analysis is carried out after formulationpreparation and at appropriate time intervals thereafter. The samplesare typically stored in controlled temperature incubators at one or moreof 5° C., 25° C. and 40° C. for several weeks or months. At appropriatetime intervals samples are removed from the incubators and theconcentration of active agent and/or a degradation product is measured.

Example 2—Oleaginous Formulations with Low Viscosity

The different hydrophobic solvents suitable for use in topicalpharmaceutical compositions are generally liquid oils that have a lowviscosity. When these oils are used as-is for active agents topicaldelivery, they have inter alia two non desirable properties: (1) becauseof their low viscosity, they tend to drop and to be runny and thereforenot easy for the patient to apply onto the skin, (2) they have poorsuspending properties leading to the rapid sedimentation ofnon-dissolved active ingredients (APIs), as described in Table 2.

TABLE 2 Low viscosity oleaginous preparations Formulations 001P 001 002P002 008P 008 Ingredients % w/w % w/w % w/w % w/w % w/w % w/w Heavymineral 75.00 75.00 — — — — oil Light mineral 25.00 25.00 — — — — oilSoybean oil — — 100 100 — — Petrolatum — — — — 50 50 C12-C15 alkyl — — —— 50 50 benzoate Total 100.00 100.00 100.00 100.00 100.00 100.00Minocycline — 0.1 — 0.1 — 0.1 HCl Results Viscosity at 96 92 47 49 488303 10 rpm (cP)

As shown in formulations 001P and 002P, mixtures of mineral oils andsoybean oil have a low viscosity. Formulations 001 and 002 show thatafter the addition of Minocycline HCl, the viscosity of the formulationremains unchanged and that the active ingredient sediments (as observedvisually).

Similarly, as shown in formulations 008P and 008, the viscosity ofmixtures of petrolatum and alkyl benzoate remains unchanged after theaddition of Minocycline HCl.

Example 3—Oleaginous Formulations with High Viscosity

The influence of the combination of a tetracycline with fatty alcohols,fatty acids and waxes on formulation viscosity was assessed, asdescribed in Table 3a. Formulations were prepared containing petrolatumor coconut oil, alone or in combination with fatty alcohols or fattyacids, and their viscosity was measured before and after the addition of0.1% of a tetracycline, namely Minocycline HCl. Table 3 below presentsthe results of formulation viscosity before and after the addition of atetracycline, as well as the percentage of viscosity increase due to theaddition of the active ingredient. Apparently, as observed in thisexperiment, when the viscosity of the composition without minocycline ishigh, such as about or more than 25,000 cPs, the synergistic effectbetween the minocycline (at a low level of 0.1%) and the second rheologymodifying agent is not discernable or is not expressed or does notprevail.

TABLE 3 High viscosity oleaginous preparations Formulations 018 019 020021 022 023 Ingredients % w/w % w/w % w/w % w/w % w/w % w/w Petrolatum100 90 90 90 — — Coconut oil — — — — 100 90 Stearyl alcohol — 10 — 5 —10 Stearic acid — — 10 5 — — Total 100.00 100.00 100.00 100.00 100.00100.00 Viscosity Results at 10 rpm (cP) Without Minocycline HCl 1769224347 21611 41511 20604 24571 With 0.1% Minocycline HCl 20252 2149922011 40151 19340 22459 % Viscosity Change +14% −12% +2% −3% −6% −9%

Example 4—Mineral Oil-Based Formulations with Controlled Viscosity

Part A—Combination of a Tetracycline with a Fatty Alcohol, a Fatty Acidor a Wax

The influence of the combination of a tetracycline with fatty alcohols,fatty acids and waxes on formulation viscosity was assessed, asdescribed in Table 4a. Formulations containing a mixture of mineral oilswith fatty alcohols, fatty acids, waxes and combinations thereof wereprepared, and their viscosity was measured before and after the additionof a tetracycline, namely Minocycline HCl. Table 4a below presents theresults of formulation viscosity before and after the addition of atetracycline, as well as the percentage of viscosity increase due to theaddition of the active ingredient.

TABLE 4a Combination of a tetracycline with fatty alcohols, fatty acidand waxes Formulations 003 004 005 024 027 036 028 Ingredients % w/w %w/w % w/w % w/w % w/w % w/w % w/w Heavy mineral oil 65 65 65 65 65 65 65Light mineral oil 25 25 25 30 25 25 25 Stearyl alcohol 10 — — — 5 — 5Stearic acid — 10 — — — 5 — Beeswax — — 10 — — — 2.5 Hydrogenated castoroil — — — 5 5 5 2.5 Total 100.00 100.00 100.00 100.00 100.00 100.00100.00 Viscosity Results at 10 rpm (cP) Without Minocycline HCl 951 1858942 848 10718 6719 5823 With 0.1% Minocycline HCl 2652 8142 1695 622338936 26762 16924 % Viscosity Change +179% +338% +80% +634% +263% +298%+191%

Surprisingly, it was discovered that the addition of minocycline HCl tomineral oil-based formulations 003 to 005 led to a substantial increasein viscosity, despite the very low concentration of minocycline HCLused, namely 0.1%. These totally unexpected results show that thecombination of a tetracycline, even at very low concentrations, withfatty alcohols, or fatty acids or waxes has a strong synergistic effecton oleaginous formulation viscosity. Without being bound by any theoryit seems that tetracyclines can interact with fatty acids or fattyalcohols to produce a rheology viscosity effect and may interact toform—without being bound by any theory a complex of some sort in theformulation, which provides for the rheology effect observed.

As shown in formulations 027, 036 and 028, the same effect of lowconcentrations of tetracycline on formulation viscosity is observed whenthe oleaginous composition contains a combination of a fatty alcohol orfatty acid with hydrogenated castor oil, with or without beeswax.

The results also indicate a strong role for hydrogenated caster oil as arheology modulator in combination with minocycline as well as on its ownto a lesser extent.

Part B—Combination of a Tetracycline with Different Fatty Alcohols

The influence of the combination of a tetracycline with different fattyalcohols on formulation viscosity was assessed, as described in Table4b. Formulations containing a mixture of mineral oils with differentfatty alcohols were prepared, and their viscosity was measured beforeand after the addition of a tetracycline, namely minocycline HCl. Table4b below presents the results and shows, the percentage of viscositychange due to the addition of the active ingredient.

TABLE 4b Combination of a tetracycline with different fatty alcoholsFormulations 037 038 039 041 Ingredients % w/w % w/w % w/w % w/w Heavymineral oil 65 65 65 65 Light mineral oil 25 25 25 25 Myristyl alcohol10 — — — Cetyl alcohol — 10 — — Stearyl alcohol — — 10 — Behenyl alcohol— — — 10 Total 100.00 100.00 100.00 100.00 Viscosity Results at 10 rpm(cP) Without Minocycline HCl 336 1808 960 5679 With 0.1% Minocycline HCl1040 5775 4591 6527 % Viscosity Change +210% +219% +378% +15%

The results indicate that an increase in formulation viscosity uponaddition of Minocyclineminocycline HCl is observed with myristylalcohol, cetyl alcohol and stearyl alcohol. However, in this experimentthe corresponding effect of behenyl alcohol alone (with low minocyclineconcentration) is lower.

Part C—Formulation with Increased Viscosity and Various Concentrationsof Minocycline

The influence of the combination of different concentrations of atetracycline with fatty alcohols, fatty acids, waxes and combinationsthereof on formulation viscosity was assessed, as described in Table 4c.Formulations containing a mixture of mineral oils with fatty alcohols,fatty acids, waxes and combinations thereof were prepared, and theirviscosity was measured before and after the addition of differentconcentrations of a tetracycline, namely minocycline HCl.

TABLE 4c Formulation with increased viscosity and various concentrationsof Minocycline Formulations 014 015 016 017 024 Ingredients % w/w % w/w% w/w % w/w % w/w Heavy mineral oil 65 65 65 65 65 Light mineral oil 3030 30 30 30 Stearyl alcohol 5 — — 2.5 1.25 Stearic acid — 5 — — 1.25Beeswax — — — — 1.25 Hydrogenated castor oil — — 5 2.5 1.25 Total 100.00100.00 100.00 100.00 100.00 Viscosity Results at 10 rpm (cP) WithoutMinocycline HCl 152 135 848 4527 2815 With 0.1% Minocycline HCl 234 7796223 7007 4191 % Viscosity Change  +54% +477% +634%  +55%  +49% WithoutMinocycline HCl 152 135 848 4527 2815 With 0.5% Minocycline HCl 12121107 14973 12717 9054 % Viscosity Change +697% +720% +1666%  +181% +222%Without Minocycline HCl 152 135 848 4527 2815 With 1.0% Minocycline HCl878 819 20108 10510 7806 % Viscosity Change +478% +507% +2271%  +132%+177%

Surprisingly, it was discovered that the addition of minocycline HCl tomineral oil-based formulations 014 to 017 and 024, containing as low as5% of a fatty alcohol, a fatty acid a wax and combinations thereof, ledto a very substantial increase in viscosity, where the increase inviscosity is dependent of the concentration of the active ingredient. Itwas noticed that formulations having a higher concentration of activeingredient have a higher viscosity.

Therefore, the combination of a tetracycline with a fatty alcohol, afatty acid and/or a wax has a strong synergistic effect in the viscosityof oleaginous formulation. The results may indicate that subject to thesecond rheology agent used the effect of a certain concentration oftetracycline may reach a plateau or peak beyond which increasing theamount of minocycline will not significantly increase the rheologyeffect as reflected in the viscosity measurements.

A first glass vial was filed with a placebo of formulation 016, and asecond glass vial was filed with formulation 016 containing 0.1%minocycline HCl. As depicted in FIG. 2, both vials were photographed inhorizontal and vertical position showing that the placebo formulation isa liquid which freely flows, while the formulation containing 0.1%minocycline HCl is a semi-solid gel-like. Therefore, the addition of anamount as small as 0.1% minocycline HCl to said formulation has anoutstanding effect both of the formulation viscosity and on theformulation physical state which changes from a liquid to a semi-solid.

The influence of the addition of different concentrations of atetracycline on a mineral oils-based formulation was then studied whenthe active ingredient is combined with a mixture of mineral oils, fattyalcohols, fatty acids and waxes, as described in Table 4d and 4e.

TABLE 4d Oleaginous stock formulation Stock Formulation 238P Ingredients% w/w Heavy mineral oil 59.25 Light mineral oil 25.00 Cyclomethicone5.00 Stearyl alcohol 1.50 Beeswax 2.00 Stearic acid 2.00 Hydrogenatedcastor oil 1.50 Behenyl alcohol 1.00 Cetostearyl alcohol 2.50 Silicondioxide 0.25 Total 100.00

TABLE 4e Oleaginous preparations with increased viscosity Formulations238P 238A 238B 238C 238D Ingredients % w/w % w/w % w/w % w/w % w/w StockFormulation 238P 100.00 99.90 99.80 99.50 99.00 Minocycline HCl — 0.100.20 0.50 1.00 Viscosity Results at 10 rpm (cP) 6639 15789 18476 2087620748 % Viscosity Change — +138% +178% +214% +213%

The combination of a tetracycline with a mixture of mineral oils, fattyalcohols, fatty acids and waxes has a strong synergistic effect andincreases the formulation viscosity. The viscosity of a formulationcontaining 0.50% minocycline HCl is about three times higher than theviscosity of the placebo formulation. The effect on the formulationviscosity is clearly related to the concentration of the tetracycline:the higher the tetracycline concentration, the higher the viscosity ofthe formulation. In formulation 238, it appears that the viscosityincreasing effect of Minocycline HCl reaches a plateau when the activeingredient is present at a concentration of about 0.50%.

In one or more embodiments, there is provided an oleaginous formulationcontaining mineral oils and a tetracycline in synergistic combinationwith a fatty alcohol, and/or a fatty acid and/or a wax, wherein theviscosity of the formulation is increased by the addition of the activeingredient by more than about 50%, more than about 100%, more than about200%, more than about 300%, or more than about 500%.

In one or more embodiments, there is provided an oleaginous formulationcontaining hydrophobic solvents, an active ingredient in synergisticcombination with a second rheology modulator, wherein the viscosity ofthe formulation is increased by the addition of the active ingredient bymore than about 50%, more than about 100%, more than about 200%, morethan about 300%, or more than about 500%.

In one or more embodiments, the increase in the formulation viscosity isrelated to the concentration of the active agent.

In one or more embodiments, the viscosity of the formulation isproportional to the concentration of the active agent: the higher theconcentration of the active ingredient, the higher the formulationviscosity.

In one or more embodiments, the viscosity increasing effect of theactive ingredient reaches a plateau when the concentration of the activeingredient is increased.

In one or more embodiments, the viscosity of the formulation containingthe active ingredient is at least twice the viscosity of the sampleformulation without the active ingredient when the active ingredientwhen present is present at a concentration of less than about 10%, lessthan about 5%, less than about 1%, less than about 0.5%, less than about0.1%, less than about 0.05%, or less than about 0.01%.

Example 5—Mixture of Petrolatum and Mineral Oil-Based Formulations withIncreased Viscosity

In formulation based on petrolatum and various amounts of mineral oil,the influence of the combination of a tetracycline with fatty alcoholson formulation viscosity was assessed, as described in Table 5.Formulations containing a mixture of petrolatum and light mineral oilwith a fatty alcohol were prepared, and their viscosity was measuredbefore and after the addition of a tetracycline, namely minocycline HCl.

TABLE 5 Petrolatum and Mineral oil-based formulations with increasedviscosity Formulations 009 010 011 012 013 Ingredients % w/w % w/w % w/w% w/w % w/w Petrolatum 90 65 40 15 10 Light Mineral oil — 25 50 75 90Stearyl alcohol 10 10 10 10 10 Total 100.00 100.00 100.00 100.00 110.00Viscosity Results at 10 rpm (cP) Without 26234 10510 3263 378 341Minocycline HCl With 0.1% 28058 12254 5039 1204 1307 Minocycline HCl %Viscosity +7% +17% +54% +219% +283% Change

When the viscosity of the placebo formulation is high, as in formulation009, and the concentration of minocyline is low (e.g. 0.1%) nosignificant increase in viscosity was noticed. Formulation 010, whichcontains low amounts of mineral oil, exhibited a minor increase inviscosity upon the addition of 0.1% minocycline HCl (which with higheramounts of minocycline could have been more substantial). However, verysurprisingly, it was observed that the addition of a very low amount ofminocycline HCl greatly increases formulation viscosity, when theviscosity of the placebo formulation is lower, as in formulations 011,012 and 013, which contain increasingly higher amounts of mineral oil.

As shown in FIG. 1, the percentage of change in viscosity by theaddition of Minocycline HCl is exponentially related to the viscosity ofthe formulation placebo.

In one or more embodiments, there is provided an oleaginous formulationcontaining hydrophobic solvents and a tetracycline in synergisticcombination with a fatty alcohol, wherein the viscosity of theformulation is increased by the addition of the active ingredient bymore than about 50%, more than about 100%, more than about 200%, morethan about 300%, more than about 500%.

In one or more embodiments, the lower the viscosity of the placeboformulation, the greater the increase in formulation viscosity afteraddition of the active ingredient.

Example 6—Other Oils-Based Formulations with Increased Viscosity

The influence of the addition of a tetracycline on vegetable oils-basedformulations was then studied when the active ingredient is combinedwith a mixture of vegetable oils, fatty alcohols, fatty acids and waxes,as described in Table 6.

TABLE 6 Formulation based on vegetable oils with increased viscosityFormulations 244P 244B 244A Ingredients % w/w % w/w % w/w Soybean oil50.00 50.00 50.00 Coconut oil 23.60 23.60 23.60 Light Mineral oil 5.554.40 0.95 Cyclomethicone 5.00 5.00 5.00 Cetostearyl alcohol 3.50 3.503.50 Stearic acid 3.00 3.00 3.00 Myristyl alcohol 2.50 2.50 2.50Hydrogenated castor oil 2.00 2.00 2.00 Beeswax 2.00 2.00 2.00 Stearylalcohol 1.50 1.50 1.50 Behenyl alcohol 1.10 1.10 1.10 Silicon dioxide0.25 0.25 0.25 Total 100.00 100.00 100.00 Minocycline HCl — 1.15 4.60Viscosity Results at 10 rpm (cP) 7214 14429 17084 % Viscosity Change —+100% +137%

The combination of a tetracycline with a mixture of vegetable oils,fatty alcohols, fatty acids and waxes has a strong synergistic effectand increases the formulation viscosity. The viscosity of a formulationcontaining 1.15% minocycline HCl is about twice higher than theviscosity of the placebo formulation. Moreover, the effect on theformulation viscosity is directly related to the concentration of thetetracycline: the higher the tetracycline concentration, the higher theviscosity of the formulation. Formulation 244 is a solid gel whichspreads easily upon application of shear force.

In one or more embodiments, there is provided an oleaginous formulationcontaining vegetable oils and a tetracycline in synergistic combinationwith a fatty alcohol, a fatty acid and a wax, wherein the viscosity ofthe formulation is increased by the addition of the active ingredient bymore than about 50%, more than about 100%, more than about 200%, morethan about 300%, or more than about 500%.

Example 7—Stability of a Tetracycline in Viscosity ControlledFormulations

Tetracycline antibiotics are known to be very unstable active agentsthat are degraded by a wide range of commonly used pharmaceuticalexcipients. For example, it has been found that minocycline is degradedin 1 to 2 days in the presence of various hydrophilic solvents (such aswater, glycerin, sodium PCA, propylene glycol and polyethylene glycols),by water dispersed polymers (such as xanthan gum, poloxamers, carbomers,methocel, sodium carboxymethylcellulose) and by surfactants (such aspolysorbates, sorbitan esters, polyoxyalkyl esters and lanolin-basedsurfactants). Thus, the achievement of a long term stable formulation oftetracycline antibiotics described herein, was a major challenge andrequired both extensive research and creativity.

The following example illustrates the chemical stability of MinocyclineHCl (MCH) in an oleaginous formulation as described in Tables 7a. In anaccelerated stability study, samples were stored at 40° C., and theconcentration of Minocycline HCl was determined by chromatographicmethods. The stability test results following, 3 weeks and 6 months ofstorage at 40° C. are shown in Table 7b.

TABLE 7a Composition of formulation incubated at 40° C. Formulations244B Ingredients % w/w Soybean oil 50.00 Coconut oil 23.60 Light Mineraloil 4.40 Cyclomethicone 5.00 Cetostearyl alcohol 3.50 Stearic acid 3.00Myristyl alcohol 2.50 Hydrogenated castor oil 2.00 Beeswax 2.00 Stearylalcohol 1.50 Behenyl alcohol 1.10 Silicon dioxide 0.25 Total 100.00Minocycline HCl 1.11

TABLE 7b Analytical Stability results of composition 244B containingMinocycline HCl after 3 after 6 weeks months T0 at 40° C. at 40° C.Minocycline 101.5% 99.1% 95.3% content (%)

Very surprisingly, and despite the known instability of tetracyclineantibiotics, the accelerated stability results of formulation 244B after3 weeks and 6 months at 40° C. showed minimal degradation of the activeagent in the formulations. The formulations disclosed herein thus showan extended accelerated stability for the tetracycline antibiotic activeagent, an outstanding physical stability, wherein the viscosity of theformulation is substantially increased by the addition of the activeingredient.

In another experiment, a sample of formulation 244B was stored during 6months at 40° C. and tested for active ingredient content uniformity andphysical stability. It was found that minocycline HCl was homogeneouslydispersed into formulation even after prolonged incubation at 40° C.Furthermore, it was found that the formulation remained as a homogeneousgel after 6 months of incubation at 40° C.

In one or more embodiments, there is provided a formulation wherein theactive ingredient is homogeneously dispersed in the formulation andremains homogeneously dispersed after 6 months of incubation at 40° C.

Example 8—Formulations with Improved Viscosity and Various ActiveIngredients

Formulation with different active ingredients were prepared as describedin Table 8a, to study the influence of the combination of various activeingredients with a fatty alcohol on formulation viscosity.

TABLE 8a Formulations of fatty alcohol and oil with improved viscositywith various active ingredients Formulations 029 030 031 032 033Ingredients % w/w % w/w % w/w % w/w % w/w Heavy Mineral oil 65 65 65 6565 Light mineral oil 25 25 25 25 25 Stearyl alcohol 10 10 10 10 10 Total100.00 100.00 100.00 100.00 100.00 Minocycline HCl 0.05 — — — —micronized Minocycline HCl — 0.10 — — — non micronized Tetracycline HCl— — 0.10 — — Cholesterol — — — 0.10 — Benzoyl peroxide — — — — 0.10Viscosity Results at 10 rpm (cP) Placebo 1152 1152 1152 1152 1152 WithActive 2655 2128 2655 1888 2112 ingredient % Viscosity Change +130% +85%+130% +64% +83%

It was found that the increase in viscosity observed after the additionof the active ingredient minocycline is also observed with other activeingredients. A strong increase in formulation viscosity was observedwith tetracycline HCl which is another compound of the tetracyclineclass. To a lesser extent, an increase in formulation viscosity wasobserved with Cholesterol which is also a 4-ring compound and withbenzoyl peroxide. It can be note that the strongest effect was observedwith tetracycline compounds, such as Minocycline HCl and TetracyclineHCl. It can be further noted that even at concentrations as low as0.05%, the addition of Minocycline HCl to the formulations more thandoubled the viscosity. It is further noted that micronized preparationsappear to have a more pronounced effect. Without being bound by anytheory a possible explanation might be that the rheology change isimproved when smaller particles are used providing a higher surface areaexposure of the active therapeutic, which facilitates more interactionswithin the composition.

Formulation with different active ingredients were prepared as describedin Table 8b and Table 8c, to study the influence of the combination ofvarious active ingredients with a wax on formulation viscosity.

TABLE 8b Formulations of wax and oil with improved viscosity withvarious active ingredients (continued) Formulations 042 043 044 045 046047 048 049 Ingredients % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/wHeavy Mineral oil 65 65 65 65 65 65 65 65 Light mineral oil 30 30 30 3030 30 30 30 Hydrogenated Castor oil 5 5 5 5 5 5 5 5 Total 100.00 100.00100.00 100.00 100.00 100.00 100.00 100.00 Minocycline HCl micronized0.10 — — — — — — — Minocycline HCl non micronized — 0.10 — — — — — —Tetracycline HCl — — 0.10 — — — — — Cholesterol — — — 0.10 — — — —Benzoyl peroxide — — — — 0.10 — — — Mometasone Furoate — — — — — 0.10 —— Doxycycline Hyclate — — — — — — 0.10 — Salicylic acid — — — — — — —0.10 Viscosity Results at 10 rpm (cP) Placebo 816 816 816 816 816 816816 816 With Active ingredient 3343 13357 8126 2415 7039 10606 7566 8974% Viscosity Change +310% +1537% +896% +196% +763% +1200% +827% +1000%

TABLE 8c Formulations of wax and oil with improved viscosity withvarious active ingredients (further continued) Formulations 050 051 052053 054 055 056 Ingredients % w/w % w/w % w/w % w/w % w/w % w/w % w/wHeavy Mineral oil 65 65 65 65 65 65 65 Light mineral oil 30 30 30 30 3030 30 Hydrogenated Castor oil 5 5 5 5 5 5 5 Total 100.00 100.00 100.00100.00 100.00 100.00 100.00 Vitamin E 0.10 — — — — — — Diclofenac — 0.10— — — — — Urea — — 0.10 — — — — Terbinafine — — — 0.10 — — — Permethrin— — — — 0.10 — — Metronidazole — — — — — 0.10 — Pimecrolimus — — — — — —0.10 Viscosity Results at 10 rpm (cP) Placebo 816 816 816 816 816 816816 With Active ingredient 7310 5663 5551 12733 6623 11246 12909 %Viscosity Change +796% +594% +580% +1461% +712% +1278% +1482%

It was noted that after various active ingredient were added separatelyto an oil and wax oleaginous formulation a viscosity increase isobserved over a wide range of active ingredients.

Example 9—Formulation with Beeswax Alone in Mineral Oil

The influence of a low concentration of tetracycline with beeswax onformulation viscosity was compared in Table 9.

TABLE 9 Oleaginous preparations Formulations 005 Ingredients % w/w Heavymineral oil 65 Light mineral oil 25 Beeswax 10 Total 100.00 ViscosityResults at 10 rpm (cP) Without Minocycline HCl 942 With 0.1% MinocyclineHCl 1695 % Viscosity Change +80%

Example 10—Compatibility Study

Procedure: Minocycline hydrochloride (“MCH”) was incubated as asuspension with various excipients at 25° C. and 40° C. for maximum ofsixty days or to the point where degradation was suspected. The ratiobetween MCH and the tested excipient is detailed below. Visualinspection was the major criterion for indication of compatibility. Thecolor of intact MCH suspension is pale yellow; and any change of color(e.g., to dark orange, red, green, brown and black) indicates oxidationor degradation.

Hydrophilic solvents were tested for compatibility with MCH at a ratioof MCH:excipient of 1:250. Dimethyl Isosorbide, Glycerin, Ethanol,Propylene glycol, Butylene Glycol, PEG 200, Hexylene Glycol, PEG 400,Dimethyl Sulfoxide and Diethylene glycol monoethyl ether were found tobe incompatible with MCH.

Oily emollients and waxes were tested for compatibility with MCH at aratio of MCH:excipient of 1:250 for Oily emollients and 1:50 for waxes.Hydrogenated castor oil, Castor oil, Cocoglycerides, Disopropyl adipate,Mineral oil light, Coconut oil, Beeswax, MCT oil, Cyclomethicone,Isododecane, Cetearyl octanoate, Gelled mineral oil, Isopropylmyristate, PPG 15 stearyl ether, Mineral oil heavy, Octyl dodecanol,White Petrolatum, Petrolatum (Sofmetic), Paraffin 42-44, Paraffin 51-53,Paraffin 56-62, Calendula oil, Shea butter, Grape seed oil, Almond oil,Jojoba oil, Avocado oil, Peanut oil, Wheat germ oil and Hard Fat werefound to be compatible with MCH. Pomegranate seed oil was found to beincompatible with MCH.

The compatibility of MCH with hydrophobic surfactant was testedfollowing solubilization of the surfactant in mineral oil (mineral oilwas previously shown to be compatible with MCH). Surfactants were testedfor compatibility with MCH at a ratio of MCH:excipient of 1:50. PEG150distearate, Laureth 4, PEG 40 hydrogenated castor oil, PEG 75 lanolin,Glucam P20 distearate, PEG100 stearate, Glyceryl monostearate, PEG 40stearate, Montanov S (Cocoyl Alcohol (and) C12-20 Alkyl Glucoside)),Alkyl lactate, Benton gel, SPAN 60, Sorbitan sesquistearate, SPAN 40,Tween 20, Ceteth 2, Sucrose stearic acid esters D1813, Ceteareth 20,Steareth 2/Steareth 21, Methyl glucose sesquistearate, Oleth 20, PPG 20methyl glucose ether, Tween 60 were found to be incompatible with MCH.Sucrose stearic acid esters D1803, Sucrose stearic acid esters D1807 andSucrose stearic acid esters D1811 were found to be compatible with MCH;however, not all of them dissolved in oil (e.g. 1811, 1813).

Foam adjuvants were tested for compatibility with MCH at a ratio ofMCH:excipient of 1:50. Isostearyl alcohol, Behenyl alcohol, Stearylalcohol, Cetyl alcohol, Oleyl alcohol, Myristyl alcohol, Cetostearylalcohol, Palmitic acid, Stearic acid and Oleic acid were found to becompatible with MCH. Isostearic acid was not compatible with MCH.

Additives were tested for compatibility with MCH at a ratio ofMCH:excipient of 1:50. Aerosil and Menthol were found to be compatiblewith MCH. Titanium dioxide and Ethocel were not compatible with MCH.

Additives were tested for compatibility with MCH. Minimal quantities ofwater (1004) were added to MCH, suspended in excipients that haddemonstrated compatibility to examine whether water can enhanceoxidation/degradation in the absence or presence of antioxidant. Inparallel, antioxidants were added to the MCH suspensions comprisingwater. Antioxidants were also added to excipients which were found to benon compatible with MCH. Addition of water caused prompt degradation ofMCH. Addition of the antioxidants alpha-tocopherol, BHA/BHT and propylgallate did not prevent MCH degradation. Compatible excipients becameincompatible in the presence of water. Addition of antioxidants did notalter this result.

1. (canceled)
 2. A method of treating acne, comprising administrating afoam composition comprising: a) a combination of at least one fattyalcohol and at least one wax; or a combination of at least one fattyalcohol, at least one fatty acid, and at least one wax; b) at least onehydrophobic solvent; and c) a minocycline at a concentration betweenabout 0.2% and about 20% by weight of the composition; wherein thecomposition is free of surfactant; wherein the composition isessentially waterless; wherein the ratio of (1) fatty alcohol to wax or(2) fatty alcohol and fatty acid to wax is between about 1:3 and about3:1; and wherein the wax comprises a mixture of beeswax and hydrogenatedcastor oil.
 3. The method of claim 2, wherein the minocycline is presentin a free base form, a hydrate form, a salt form, or a complex form. 4.The method of claim 2, wherein the foam composition further comprises atetracycline, an oxytetracycline, a demeclocycline, a doxycycline, alymecycline, a meclocycline, a methacycline, a rolitetracycline, achlorotetracycline, a tigecycline, or a mixture of two or more thereof.5. The method of claim 2, wherein the foam composition further comprisesa doxycycline.
 6. The method of claim 2, wherein the concentration ofthe minocycline is between about 1% and about 10% by weight of thecomposition.
 7. The method of claim 2, wherein the concentration of theminocycline is between about 1% and about 4% by weight of thecomposition.
 8. The method of claim 2, wherein the concentration of theminocycline is about 4% by weight of the composition.
 9. The method ofclaim 2, wherein the concentration of the minocycline is about 1% byweight of the composition.
 10. The method of claim 2, wherein the atleast one fatty alcohol comprises 14 carbon atoms in its backbone. 11.The method of claim 2, wherein the fatty alcohol comprises stearylalcohol, cetostearyl alcohol, behenyl alcohol, and/or myristyl alcohol.12. The method of claim 2, wherein the at least one fatty alcohol ispresent at a concentration from about 0.1% to about 20% by weight of thecomposition.
 13. The method of claim 2, wherein the at least one waxand/or the at least one fatty acid is present at a concentration fromabout 0.1% to about 20% by weight of the composition.
 14. The method ofclaim 2, wherein the hydrophobic solvent comprises soybean oil, coconutoil, cyclomethicone, and/or mineral oil.
 15. The method of claim 2,wherein the hydrophobic solvent is present at a concentration from about60% to about 95% by weight of the composition.
 16. The method of claim2, wherein the foam composition further comprises a silicon dioxide. 17.The method of claim 2, wherein the foam composition further comprises abenzoyl peroxide.
 18. The method of claim 2, wherein the wax comprises amixture of beeswax and hydrogenated castor oil at a ratio of about 1:1.19. The method of claim 2, wherein the acne is acne vulgaris.